Ongoing projects

Towards an end-to-end solution for unbiased cellular phenotyping of intact cerebral organoids. 01/11/2022 - 31/10/2024

Abstract

The cerebral organoid is an emerging model system with high potential for both fundamental and applied neuroscience research. However, batch-to-batch variability and the inability to characterize these specimens at the cellular level with high throughput, hampers their integration in an industrial setting. With this project, we intend to develop a pipeline that enables unbiased cellular phenotyping of intact cerebral organoids by using a combination of multiplex fluorescent labelling, light-sheet microscopy, and deep learning. Our approach builds on the concept that cells can be accurately identified by means of sheer morphological information. First, we will perfection cell profiling in co-cultures of different brain cell lines by training machine learning-based classifiers. Then, we will translate the concept to 3D, using spheroids from the same cells. To this end, we will render the staining compatible with chemical clearing and conceive a sample mounting procedure for serial, isotropic image acquisition. Finally, we will deploy the optimized method to recognize cell type and state in iPSC-derived cerebral organoids that have been challenged with selected compounds or seeded with glioblastoma cells. The approach will add to a more standardized quality-control of organoids and will facilitate the adoption of this model in drug-screening pipelines. Ultimately, this will boost the translatability of preclinical research and lower attrition rates in late-stage clinical trials.

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  • Research Project

Advanced Centre for Advanced Microscopy (ACAM). 01/01/2022 - 31/12/2026

Abstract

The Antwerp Centre for Advanced Microscopy (ACAM) provides high-end service for visualizing biological samples from the nano- to the mesoscale. Its mission is to be the go-to hub for demanding microscopy-oriented work and to exploit its quantitative imaging expertise to foster research excellence at the University of Antwerp. To do so, ACAM assists with project planning, sample preparation, microscope selection and use, image analysis and visualization, and data interpretation. ACAM manages 10 advanced microscope systems, a server for image data warehousing and several workstations for image analysis. High-dimensional imaging is a major focus with light sheet microscopy, ultrafast live cell imaging and high-throughput screening as flagship technologies. Next to novel hardware acquisition and maintenance, ACAM develops its own software algorithms and evaluates experimental accessory setups. Routine training and thematic courses are organized to assure apt knowledge transfer regarding new technologies, optimal equipment usage and experimental reproducibility. ACAM pursues an open science policy and invests in making its data adhere to FAIR data principles. By combining breadth and depth in offered technology, and by keeping the pulse of the rapidly developing imaging field, ACAM aims at empowering researchers to perform science with high impact.

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Nuclear envelope stress in laminopathy patient-derived cardiomyocytes (NStrC). 01/01/2022 - 31/12/2025

Abstract

Dilated cardiomyopathy is the primary cause of heart transplants worldwide. Hereditary variants of the disease are driven by mutations in the LMNA gene, which encodes A-type lamins, structural components of the nuclear envelope (NE). The pleiotropic nature of lamins and the limited availability of patient material complicate the identification of pathological processes underlying heart failure. We and others have shown that lamin perturbations predispose cells for nuclear dysmorphy and rupture, which compromises cell homeostasis and elicits DNA damage. We hypothesize that this so-called NE stress represents a common hallmark of cardiac laminopathies. Hence, we intend to gauge the impact of pathogenic lamin variants on this process in a cellular model that is relevant to the disease. To this end, we will generate induced pluripotent stem cell-derived cardiomyocytes from cardiac patient fibroblasts harboring diverse LMNA mutations. In these cells, we will quantify structural defects of the NE and its susceptibility to rupture with advanced microscopy. In addition, we will perform a comparative transcriptomics experiment to reveal gene regulatory programs that accompany NE stress and evaluate the influence of two major NE stress elicitors by pharmacological modulation. This way, we intend to expose the role of NE stress in the development of cardiac laminopathies and unveil potential leads for its therapeutic targeting.

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Organoid painting: Unbiased cellular phenotyping of human tissue mimics using deep learning-enhanced imaging and analysis. 01/01/2022 - 31/12/2023

Abstract

Identification of novel therapeutic compounds relies on the use of cell culture and animal models. While the former are overly simplified, the latter are not human and ethically contested. Suboptimal models at the discovery side will inevitably lead to a steep loss of leads in clinical trials. With the advent of human induced pluripotent stem cell (iPSC) technology, it has now become possible to generate organoids that more faithfully capture part of the heterogeneity and three-dimensional context of human tissue. However, the complexity and optical inaccessibility of such tissue mimics hamper their adoption in a routine screening setting. We intend to develop a pipeline that will allow in-depth characterization of organoids. Concretely, we will combine our expertise in advanced microscopy and deep learning to enable ultrafast, high-quality imaging and subsequent cellular phenotyping of organoids. As two case studies with industrial relevance, we will use this pipeline to discriminate cell states in tumor spheroids and cell types in neuro-organoids. Once established, our approach will find a ready market with pharmaceutical and clinical R&D laboratories that wish to test their compound libraries on a physiologically relevant model, in particular in the oncology and neuroscience fields. In addition, it will foster an improved quality control of tissue mimics in the context of regenerative medicine.

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Tau-induced senescence in human mini-brain. 01/10/2021 - 30/09/2024

Abstract

Defects in the microtubule associated protein tau typify a range of neurodegenerative disorders termed tauopathies, which includes Alzheimer's disease. Recent studies point to the potential involvement of cellular senescence, an irreversible non-proliferative state, associated with inflammatory cytokine secretion, in disease development. However, the causality, timing, and afflicted cell types remain poorly characterized. The goal of this project is to define the exact causal relationship between senescence and tauopathy development in a human context. To achieve this, I intend to produce human iPSC-derived brain organoids that contain the three major cell types of the brain (neurons, astrocytes, or microglia) and assess the emergence of senescence therein using deep coverage microscopy and single cell sequencing. Once a cell-specific senescence signature has been established, I will measure its penetrance in mutant organoids that recapitulate the hallmarks of tau pathology. Finally, I will evaluate whether senescence-targeting compounds modulate tau pathology and influence organoid condition. Together, this work should allow defining whether senescence is a driving factor in human tau pathology development and unveil its potential as druggable node.

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High resolution structure determination of therapeutically relevant proteins as a means to validate an affinity grid for cryo-electron microscopy. 01/07/2021 - 30/06/2023

Abstract

Cryo-electron microscopy (cryo-EM) has evolved tremendously over the last five years, thereby becoming a promising method to gain high-resolution structural information on proteins with a relevance in human (patho)physiology (e.g., cancer, host-pathogen interactions, and neuropathologies). This rapid evolution has sparked the interest of pharmaceutical companies in cryo-EM, since obtaining detailed structural information on proteins yields better insights into their function, which can be used to develop novel and/or better pharmaceuticals. However, as a result of its success, several inefficiencies within the cryo-EM workflow have emerged, especially related to sample preparation. Novel technologies have been proposed to optimize these, but these new techniques (i) often address only a single step within the overall workflow, (ii) are incompatible with other novel protocol/procedures or (iii) are difficult to implement by non-expert users. In a previous PoC study we developed a novel type of affinity grid that can be used for on-grid protein purification. Furthermore, market interviews have revealed that the introduction of this technology is best achieved through a service for protein structure determination (including a workflow from protein sample to protein structure) rather than simply providing the technology as such. The aim of this follow-up PoC is to validate the technology by resolving different protein structures using this grid technology and meanwhile establishing a service pipeline for high-resolution protein structure determination. This will illustrate the value of the grids towards potential customers (Pharma, Biotech) and investors.

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IMARK. Network for image-based biomarker discovery and evaluation 01/01/2021 - 31/12/2026

Abstract

IMARK capitalizes on the deeply rooted expertise in biomedical imaging at the University of Antwerp to push the boundaries of precision medicine. By resolving molecular and structural patterns in space and time, IMARK aims at expediting biomarker discovery and development. To this end, it unites research groups with complementary knowledge and tools that cover all aspects of imaging-centred fundamental research, preclinical validation and clinical evaluation. IMARK harbours high-end infrastructure for electron and light microscopy, mass spectrometry imaging, magnetic resonance imaging, computed tomography, positron emission tomography and single-photon emission computed tomography. Moreover, IMARK members actively develop correlative approaches that involve multiple imaging modalities to enrich information content, and conceive dedicated image analysis pipelines to obtain robust, quantitative readouts. This unique blend of technologies places IMARK in an excellent position as preferential partner for public-private collaborations and offers strategic advantage for expanding the flourishing IP portfolio. The major application fields of the consortium are neuroscience and oncology. With partners from the Antwerp University Hospital and University Psychiatric Centre Duffel, there is direct access to patient data/samples and potential for translational studies.

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Connecting European Cohorts to Increase Common and Effective Response to SARS-CoV-2 Pandemic (ORCHESTRA). 01/12/2020 - 30/11/2023

Abstract

The ORCHESTRA project provides an innovative approach to learn from the SARS-CoV-2 health crisis and derive recommendations for increasing preparedness for future outbreaks. The main outcome of the project is the creation of a new pan-European cohort built on existing and new large-scale population cohorts in European and non-European countries. Data analysis through a federated learning technique supported by advanced modelling capabilities will allow the integration of epidemiological, clinical, microbiological and genotypic aspects of population-based cohorts with environment and socio-economic features. The ORCHESTRA cohort will include SARS-CoV-2 infected and non-infected individuals of all ages and conditions and thereby enabling a retrospective evaluation of risk factors for the disease acquisition and progression of the disease and prospective follow-up aimed at exploring longterm consequences and analysis of vaccination response when vaccines will be available. To better address these research questions, the ORCHESTRA-cohort will include adequately sampled representatives of general populations, COVID-19 patients and special 'at risk' populations of fragile individuals and health-care workers. The project will assess also health costs of COVID-19 with special emphasis on delayed health services in the fragile populations. The participation of non-European and Low-Medium Income Countries and a Global COVID-19 Guidance group of major stakeholders and investigators from successful clinical trials addressing therapeutic approaches to COVID-19, ensures inclusion of all expertise needed and translation of recommendations to different social and economic settings. The project will significantly impact on the responsiveness to SARS-CoV-2 and can be used as a model for responsiveness for new public health threats. Specifically, in this work package, different cytokines and chemokines from blood of COVID-19 patients will be studied and markers predicting disease severity, mortality, and/or long term sequalae will be identified in collaboration with other partners of ORCHESTRA.

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Enteric Neuro-Immune units (eNIu) as sensors of environmental factors, their role in gut homeostasis (health and disease) and their impact on brain-gut axis physiology 01/10/2020 - 30/09/2025

Abstract

Immunological studies are crucial for the Public health, as they provide knowledge for the development of new treatments against inflammatory or autoimmune diseases. One of the major concerns in gastro-intestinal medicine is to understand how in the mucosal environment Neuro-Immune units can promote health or disease. Tackling these aspects requires genetic, cellular and molecular studies, which despite new technological progress in the last years, still remain to be elucidated. The Gastrointestinal (GI) tract is the centre of absorption and secretion, which is essential for growth, digestion, and protection against pathogenic microorganisms. Inflammatory Bowel Diseases (IBD), including Ulcerative colitis (UC), Crohn's disease (CD) and Colorectal cancer (CRC) are multifactorial, heterogenous and chronic idiopathic disorders that cause inflammation of the gastro-intestinal tract, in which inadequate host-microbe relationship leads to a breakdown of intestinal homeostasis. The 'rise' of IBD and CRC in developed countries can be attributed to an increasingly ageing population, unfavourable modern dietary habits, inadequate physical exercise, environmental factors (sporadic development) or genetic factors. IBD and CRC are considered to be the wound that will never heal. Both diseases are characterised by a long chronic inflammatory pathology, and treatment strategies focuses on immune suppressive drugs that target cytokines and their receptor1, chemical elimination or surgery, although these treatments are not curative. Recently, it was reported that there is a probable connection between cancer, IBD and tissue repair, although the phenotypes of cellular pathology could diverge in some minor details. Nevertheless, the greater challenge remains particularly to target patients who do not respond or who lose response to treatment. To improve therapeutic design and implement new effective treatments of IBD and CRC, it will thus be necessary to increase the knowledge of how intestinal barrier homeostasis is supported by the microenvironment, constituting of stromal cells, and Neuro-Immune units. My future independent research is focused on Enteric Neuro-Immune units (eNIu) as sensors of environmental factors, their role in gut homeostasis (health and disease) and their impact on brain-gut axis physiology. The main aim is to understand how different environments imprint on eNIu to induce inflammation or health/repair, and to identify the local inter- and intra-cellular networks and connections with the central nervous system (CNS). This work will shed light on enteric Neuro-Immune units during IBD, opening new and personalised therapy opportunities for fibrosis associated to resistant IBD or to UC-CRC, and CRC patients.

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Role of enteric Neuro-Immune units in mucosal homeostasis. 01/10/2020 - 30/09/2024

Abstract

One of the major concerns in gastro-intestinal medicine is to understand how in the mucosal environment Neuro-Immune units can promote health or disease. Tackling these aspects requires genetic, cellular and molecular studies, which despite new technological progress in the last years, still remain to be elucidated. Inflammatory Bowel Disease (IBD) are considered to be the wound that will never heal, which is characterized by a long chronic inflammatory pathology, and treatment strategies focuses on immune suppressive drugs or surgery, although these treatments are not curative. Nevertheless, the greater challenge remains particularly to target patients who do not respond or who lose response to treatment. To improve therapeutic design and implement new effective treatments of IBD, it will thus be necessary to increase the knowledge of how intestinal barrier homeostasis is supported by the microenvironment, constituting of stromal cells, and Neuro-Immune units. The main aim is to understand how different environments imprint on eNIU to induce inflammation or health/repair, and to identify the local inter- and intra-cellular networks and connections with the central nervous system.

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Synaptic Dysfuntion mediated by Alzheimer's disease-relevant Microglia (SynDAM). 01/07/2020 - 31/01/2023

Abstract

Recent evidence points to microglia, the central nervous system-resident macrophages, as mediators of synapse degeneration in AD. Our project aims to pinpoint the exact contribution of microglia to synapse (dys-)function by deploying an in vitro chimeric OSC platform as physiological model for functional studies of iPSC-derived human microglia, and by analysing the contribution of different microglia subpopulations to synaptic pruning in health and AD. This study will provide new hints on the protective/detrimental role of human microglial subpopulations and will be key to developing AD therapies that are capable of fine-tuning microglial composition in the beneficial direction.

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Interactive and intelligent cellomics platform. 01/05/2020 - 30/04/2024

Abstract

Crucial insights in cell and developmental biology have been gained by virtue of live cell imaging technology. Along with a growing complexity of cellular models and the finesse with which they can be genetically engineered, comes a demand for more advanced microscopy. In brief, modern comprehensive cell systems research (cellomics) requires light-efficient, intelligent and interactive imaging modalities. To address this shared need, our consortium has identified a state-of-the art platform that allows ultrafast, yet minimally invasive imaging of small to medium-sized biological samples (from single cells to organoids) at high resolution, so as to capture dynamic events that range in timescale from voltage fluctuations to successive cell divisions. To only focus on those events that are truly of interest, and thereby boost throughput, the system is equipped with online image recognition capabilities. Finally, to allow targeted perturbations such as local damage induction or optogenetic switching, small regions can be selectively illuminated in the field of view. With this level of control, it will become possible to interrogate (sub-)cellular processes with unprecedented detail. The platform readily finds applications in diverse frontline research fields including neuroscience, cardiovascular research and infectious diseases, rendering it an indispensable asset for the applicants, the microscopy core facility and the University of Antwerp.

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Gut-organ axes in health and disease 01/01/2020 - 31/12/2024

Abstract

The aim of this network initiative is to exploit collective interest and complementary expertise to enhance insight in the pathophysiological mechanisms of disorders of which we hypothesise they have common ground in the GI tract. We will investigate key areas of uncertainty regarding the exact role of intestinal barrier function (the microbiome, the epithelial barrier and the mucosal immune system) in the different gut-organ-axes and associated pathologies.

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Microglial heterogenecity and dynamics in the context of induced tau pathology. 01/01/2020 - 31/12/2022

Abstract

The major aim of this project is to characterize the response of microglia towards tau pathology and to assess the influence they might have on disease progression. To do this in an unbiased and comprehensive manner, we will perform a longitudinal experiment in which we will analyze the transcriptome of individual microglial cells from selected brain regions of a tauopathy mouse model. This work may expose novel molecular targets that could serve for early detection or therapeutic interventions in the context of AD and other neurodegenerative disorders.

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Unravelling the cellular response to photoporation. 01/01/2019 - 31/12/2022

Abstract

Delivering compounds into cells is a ubiquitous requirement for fundamental life science research and cell-based clinical applications. Since cells are protected from the outside world by their plasma membrane, it requires sophisticated technology to deliver compounds across this barrier without causing toxicity. Photoporation is emerging as a powerful technology to achieve exactly this. It relies on laser illumination of plasmonic nanoparticles that have been added to cells. Absorption of the laser energy by the nanoparticles causes the plasma membrane to become permeable by local heating or pressure effects, allowing external compounds to diffuse into the cells. While it has been amply demonstrated that photoporation does not cause acute cytotoxicity, it remains unknown how it affects cell physiology at the short and longer term. Yet, this information is crucial to safely implement the technology in different settings. Therefore, we will unravel the cellular response to photoporation. We will thereby analyse early downstream events such as the activation of membrane repair pathways and induction of cellular stress levels, as well as more persistent changes in gene expression and genome integrity. The fundamental insights from these studies will provide a solid basis for making photoporation a standard transfection technology that can be used with confidence. At the same time, it will help devise strategies to reduce or exploit potential side effects of photoporation.

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Combatting Bacterial Resistance in Europe - Molecules Against Gram Negative Infections (COMBACTE-MAGNET). 01/01/2015 - 31/12/2022

Abstract

This project represents a formal research agreement between UA and on the other hand EU. UA provides EU research results mentioned in the title of the project under the conditions as stipulated in this contract.

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Support maintenance scientific equipment (Cell biology and histology). 01/01/2005 - 31/12/2022

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Past projects

Mapping amyloid-induced neurodegeneration in the gut using MALDI imaging. 01/04/2021 - 31/03/2022

Abstract

Alzheimer's disease (AD) is the most prevailing form of dementia worldwide. In light of the aging population and absence of a cure, alternative research paths are being explored to tackle the disease at an early stage. Recent evidence suggests that the gut could play an important role in AD pathogenesis as it is continuously exposed to amyloids and is vulnerable to inflammatory stimuli that compromise its integrity. Current experimental methods for querying pathological signatures in gut tissue are either destructive or not sufficiently specific. Hence, we propose to use Matrix-Assisted Laser Desorption Ionization – Mass Spectrometry Imaging (MALDI-MSI) to quantify amyloid pathology and the associated proteomic changes in a comprehensive and spatially resolved manner. We will apply this technique to a mouse model that displays an accelerated aging phenotype, and develops the typical hallmarks of AD. To validate amyloid enrichment therein, we will make use of fluorescent markers, and as internal control, we will compare gut with brain tissue. In the spirit of the recently established valorization platform IMARK, this new collaborative initiative between the laboratory of Cell Biology and Histology and the Centre for Proteomics should facilitate the discovery of novel early biomarkers for AD in an organ that is much more accessible than the brain.

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Exploring the role of a novel mast cell activation pathway in IBD and IBS models. 01/04/2021 - 31/03/2022

Abstract

Chronic abdominal pain is one of the most debilitating and untreatable symptoms in patients suffering from Inflammatory Bowel Diseases (IBD) and Irritable Bowel Syndrome (IBS). The last years it has become clear that aberrant gut mast cell functioning plays an important role in the pathophysiology of chronic abdominal pain, but it currently remains unclear which triggers and membrane receptors are involved in driving this aberrant mast cell functioning. Therefore, from a therapeutic point of view, it is crucial to identify and characterize these triggers and membrane receptors. In this project we will focus on a newly discovered mast cell activation pathway and evaluate its role in mast cells of IBD and IBS mouse models. In this way, we want to obtain first insights into the role of this pathway as a possible new driver of aberrant mast cell functioning in IBD and IBS mouse models, which would generate a novel paradigm in IBD and IBS research and forms a solid foundation for further studies into the therapeutic potential of this pathway in these conditions.

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High-resolution slide scanner for digital histopathological phenotyping in health and disease. 01/01/2020 - 31/12/2021

Abstract

Digital pathology involves high-speed, high-resolution digital acquisition of images representing entire stained tissue sections from glass slides and allows them to be viewed directly in much the same way as standard microscopy. While this creates a permanent record of histological slide data and facilitates data sharing with collaborators, importantly, it allows analysis, quantification and objective pathological assessment of entire tissue samples, which is now current practice in pre-clinical and clinical research. We propose to acquire a high-resolution whole-slide scanner, notably absent at UA, not only to facilitate research at the promotors' groups, but virtually any research group performing basic, pre-clinical or clinical research at UA involving histopathology. We firmly believe that acquisition of such a digital scanner will help research groups at UA to stay competitive in biomedical research, facilitate and forge scientific and industrial collaborations at UA and beyond, and generate important industrial revenues.

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The impact of mixed or polymicrobial flora in the development of ventilator-associated pneumonia. 01/10/2019 - 31/05/2022

Abstract

Pneumonia is one of the most common causes of hospital-acquired infections with mortality rates reaching higher than 30%. One in 3 patients receiving mechanical ventilation develop ventilator-associated pneumonia (VAP). Despite this high incidence and mortality, the disease pathogenesis of VAP remains poorly understood. Pseudomonas aeruginosa and Staphylococcus aureus are the most common causes of VAP, and when present together, cause mortality rates of up to 50%. Recent work in our laboratory has revealed an immunosuppressive role of mechanical ventilation that likely plays a role in VAP pathogenesis. Inspired by these data – as well as a growing body of evidence that polymicrobial flora is an important cause of immunosuppression in sepsis and some other infection-related conditions, and that VAP is polymicrobial even though one or two organisms predominate – we intend to test the hypothesis that polymicrobial flora in lungs could also cause local immunosuppression and that, together with MV-induced immunosuppression, leads to growth of pathogenic bacteria in the causation of VAP. Besides this, we also intend to dissect any immunosuppressive role of Staphylococcus spp. in VAP pathogenesis as these organisms are known to have an immune-modulatory role and are frequently (co)-cultured from VAP patients. Lastly, we intend to pinpoint key interactions between P. aeruginosa and S. aureus in a humanized immune context, that together with other objectives could reveal important, and perhaps targetable steps in the pathogenesis of VAP.

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Lab-on-a-chip for cryo-EM (LOCEM). 01/10/2019 - 30/09/2021

Abstract

The general purpose of this project is the development of an optimized prototype of the total lab-on-a-chip for cryo-EM, i.e. a cryo-EM affinity grid in combination with a microfluidic chip. The latter will enable the purification of bioparticles (i.e. proteins) which will then be loaded on a cryo-EM affinity grid.

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Border control: Exposing the molecular mechanisms of nuclear envelope rupture and repair. 01/10/2019 - 30/09/2021

Abstract

The nuclear lamina is a critical regulator of nuclear structure and function. Defects in its major constituent proteins, A-type lamins, cause diseases known as laminopathies. Our group has discovered that laminopathy cells experience transient ruptures of the nuclear envelope, leading to illegitimate exchange of proteins between the cytoplasm and the nucleus. This feature contributes significantly to disease development in laminopathies, but also plays a key role in cancer. However, little is known about the underlying mechanisms. Considering its medical potential, we want to pinpoint the drivers of rupture induction and repair in a systematic manner. Using a combined strategy of molecular profiling and deep coverage microscopy we will further our understanding of the rapidly expanding tree of laminopathies, and may expose new therapeutic entry points with relevance for an even broader spectrum of lamin-associated disorders.

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Development of an affinity grid for cryo-electron microscopy enabling protein structure determination. 01/04/2019 - 31/10/2020

Abstract

Cryo-electron microscopy (cryo-EM) has evolved tremendously over the last five years, thereby becoming a promising method to gain high-resolution structural information on therapeutically relevant proteins involved in cancer, bacterial or viral infections, or neuropathologies. This rapid evolution has sparked the interest of pharmaceutical companies in cryo-EM, because protein structure information may yield better insights into the functioning of proteins, which can be used to develop better drugs. However, as a result of its success several inefficiencies within the cryo-EM workflow have emerged, especially related to sample preparation. Novel technologies have been proposed to optimize these, but these new techniques (i) often address only a single step within the overall workflow, (ii) are incompatible with other novel solutions or (iii) are difficult to implement by non-expert users. The objective of this PoC study is to revive affinity grids, electron microscopy grids that can be used for on-grid protein purification, and a potential solution to bypass some of the existing bottlenecks. by introducing novel recent developments in nanotechnology. The novel grid will be part of a larger international initiative aimed at developing an integrated workflow for highthroughput cryo-EM.

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Transcriptomic profiling of amyloid-induced responses in central and enteric neuronal cultures. 01/04/2019 - 30/03/2020

Abstract

In recent years, growing evidence has been provided showing that disorders affecting the central nervous system (CNS) are accompanied or even preceded by neuropathological alterations in the enteric nervous system (ENS). This co-morbidity is well-described for Parkinson's disease and prion diseases, but it is still unclear whether the same holds true for disorders involving β-amyloid (Aβ) accumulation such as Alzheimer's disease (AD). Until now, it is still unclear whether enteric neurons and/or associated cells within the ENS are capable of taking up and transmitting Aβ species, in the end leading to functionally impaired enteric neurons as is the case in the CNS. As a first step in addressing these questions, we want to acquire a comprehensive view on differentially expressed genes and pathways after Aβ stimulation. Therefore, primary cultures of hippocampal and myenteric neurons will be prepared and challenged with microbial (Curli) and human-derived (Aβ42 oligomers and scrambled peptide) amyloids, as well as with known inducers of an inflammatory stress response (LPS and PolyI:C). In these samples, gene expression changes will be studied using transcriptomics, followed by validation of a subset of top hits with qPCR, Western blot and immunostainings. The results obtained in this project will fuel future research into the involvement of the microbiome-gut-brain axis in AD.

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Using molecular proximity to refine synapse quantification in neuronal cultures. 01/04/2019 - 29/02/2020

Abstract

Synapses are specialized connections between neuronal cells that determine the wiring patterns, which are essential for memory and cognition. Synaptic dysfunction is a common pathological hallmark of neurodevelopmental and - degenerative conditions. Thus, accurate and reliable quantification of synaptic state and number in neuronal networks is crucial. In previous work, we have shown that primary neuronal cultures from rodents preserve many morphological and functional properties of in vivo neuronal networks and can be used to evaluate the impact of chemo-genetic perturbations on synaptic state. However, the large number of synapses on the one hand, and the variable specificity of existing microscopy techniques on the other hand, makes synapse quantification in these cultures a balancing act between accuracy and throughput. To improve both, we propose to make use of a novel method, termed Proximity Ligation Assay (PLA), that can directly visualize molecular interactions using a standard fluorescence microscope. To do so, we will first identify an optimal set of trans-synaptic protein interactors. Then, we will validate the PLA technique and use it to measure synapse density after application of targeted perturbations. By applying PLA to trans-synaptic proteins, we aim at detecting true synapses with superior specificity. This should enhance the sensitivity with which we can detect changes in synapse density, and therefore it has the potential to accelerate the identification of synaptic modulators in our ongoing screening efforts.

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    Exploring the consequences of nuclear envolope stress in cancer cells. 01/01/2019 - 31/12/2021

    Abstract

    Altered nuclear shape is a defining feature of cancer cells, but the relationship with pathology development remains elusive. Recent observations indicate that nuclear dysmorphy correlates with an enhanced propensity of nuclei to rupture. Such ruptures transiently perturb nuclear compartmentalization but also provoke DNA damage. Thus, nuclear dysmorphy and fragility – jointly referred to as nuclear envelope (NE) stress – may contribute to genome instability and thereby represent a novel emerging hallmark of cancer. To better understand the contribution of NE stress to the carcinogenic process, I propose to systematically investigate the short- and long-term molecular consequences. To this end, I intend to analyze the population-level changes in the transcriptome as well as in the genome upon targeted, temporary disruption of nuclear compartmentalisation. This way, I expect to generate a comprehensive view on the impact of NE stress on cell fate. In extensu, this work may also lead to the identification of novel synthetic lethal targets that could be exploited in clinical applications.

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    Nucleaks. Screening for regulators of nuclear envelope integrity. 01/10/2018 - 30/09/2022

    Abstract

    The nuclear lamina is a critical regulator of nuclear structure and function. Defects in its major constituent proteins, A-type lamins, cause diseases known as laminopathies. Laminopathy patient cells experience transient ruptures of the nuclear envelope, leading to uncoordinated exchange of proteins between the cytoplasm and the nucleus. This feature contributes significantly to disease development in laminopathies, but also plays a key role in cancer. However, as yet, little is known about the underlying mechanisms. We want to pinpoint the drivers of rupture induction and repair in a systematic manner. To this end, we will perform a gene-silencing screen that is based on live-cell imaging, using transient loss of nuclear compartmentalization as prime readout. To bypass the unpredictable nature of spontaneous ruptures, we will also optimize methods to mechanically induce ruptures. Putative hits that arise from the primary (spontaneous ruptures) and secondary screen (induced ruptures) will be validated and characterized by location proteomics and co-immunoprecipitation experiments. This functional genomics approach will further our understanding of laminopathy development, and may expose new therapeutic entry points with relevance for the broad spectrum of lamin-associated disorders.

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    Harnessing a therapeutic microbiome as an alleviating strategy for dysbiosis and recurrence in colorectal cancer patients undergoing radiotherapy. 01/10/2018 - 30/09/2022

    Abstract

    Colorectal cancer (CRC) is the second most common malignancy in the world. With an estimated recurrence rate of 20-30%, CRC represents an important health and socioeconomical burden. Recent data based on metagenomics and experimental models suggest a strong contribution of the gut microbiome in modulating CRC development. This project aims to understand the role of microbiome in CRC development and recurrence, specifically in studying if CRC recurrence is significantly affected by the radiation induced dysbiosis and if faecal microbiota transplantation can resolve radiation-induced dysbiosis and attenuate CRC development.

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    • Research Project

    BRAINDRAIN - Exploring the role of aquaporin 4 in clearing toxic protein aggregates from the brain. 01/10/2018 - 30/09/2022

    Abstract

    The goal of this project is to ehicidate the contribution of AQP4-mediated glymphatic function in AD development and to screen for compounds or conditions that modulate AQP4-driven pathways. To do so, we will develop and exploit innovative cell culture and manipulation techniques and use advanced 3D imaging paradigms to characterize humanized mouse models.

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    • Research Project

    Sustaining, deepening and expanding the Sub-Saharian HPV research network (WAKA-HPV Africa). 01/01/2018 - 31/08/2022

    Abstract

    Almost 90% of deaths from HPV-related invasive cervical cancer (ICC) worldwide occur in developing countries and ICC is a main cause of morbidity and mortality in Sub-Saharan Africa (SSA). However, in SSA, we observe a significant lack of ICC knowledge among health care workers. Furthermore, academic ICC expertise is also completely missing, undermining any effort to strengthen the health care capacities. Local academic expertise is also vital for National policy makers and public opinion. In 2013, we established the WAKA network to train African based researchers till a post-doc level, to stimulate international South South collaboration and to support local laboratory facilities (www.wakahpvafrica.com). Several students from SSA are in a doctoral trajectory and the WAKA network gained significant recognition (i.e. WHO). This proposal wants to continue, deepen and expand this network until a level of self-sustainability.

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    • Research Project

    Therapeutic targets in prevention and treatment of ventilator-associated pneumonia. 01/01/2018 - 31/12/2021

    Abstract

    Pneumonia is one of the most common causes of hospital-acquired infections with mortality rates reaching higher than 33%. One in 3 patients receiving mechanical ventilation develop ventilator-associated pneumonia. Despite this high incidence and mortality, the disease pathogenesis of ventilator-associated pneumonia remains poorly understood. Recent work in our laboratory has revealed an immunosuppressive role of mechanical ventilation in causation of ventilator-associated pneumonia, and would be further studied in this project.

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    • Research Project

    The peripheral component of neurodegeneration: uptake and transmission of amyloid proteins in the enteric nervous system. 01/01/2018 - 31/12/2021

    Abstract

    Since a few years, evidence is growing that a disease process affecting the central nervous system (CNS) can also involve its enteric counterpart (ENS) and vice-versa. Indeed, various neurodegenerative disorders are accompanied or even preceded by gastrointestinal malfunctions. This relationship is well-documented for prion diseases and Parkinson's disease, but has not yet been scrutinized for Alzheimer's disease (AD), a devastating neurodegenerative disorder that is typified by a progressive and debilitating cognitive decline. A defining feature of AD is the accumulation of misfolded amyloid-beta peptides. Considering that the CNS and ENS are highly interconnected, the gut microbiome produces amyloids that can cross-seed polymerization, and inflammation promotes amyloid build-up, it is highly conceivable that the gut is a vulnerable node for amyloid-driven degeneration. Yet, the mechanisms underlying cellular processing of amyloids in the ENS are poorly characterized. Hence, with this research project, we will investigate the entry routes, spreading behaviour and cellular effects of microbial and host-derived amyloid proteins in the ENS. Using innovative imaging technologies and well-defined molecular characterization methods, this work will provide a solid basis for refining the gut-brain axis theory in the context of AD and will open novel avenues for both fundamental and clinical research with relevance for a broad range of proteopathic neurodegenerative diseases.

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    • Research Project

    The peripheral component of neurodegeneration: response to and transmission of host-derived and microbial amyloid proteins in the enteric nervous system. 01/01/2018 - 31/12/2021

    Abstract

    Alzheimer's disease (AD) currently affects 1 in 9 individuals over 65 years of age but its prevalence will only rise against the background of a steadily greying population. With no cure currently available and diagnosis relying on the assessment of late-stage cognitive decline, it is imperative that novel early medical entry points are explored through original fundamental research. Recent insights suggest that the gut may be a vulnerable node for amyloid-driven neurodegeneration. That is why we want to define the origin, entry routes and spreading behaviour of amyloid proteins in the enteric nervous system (ENS). Using innovative imaging technologies and well-defined molecular analyses, we will shed light on a novel gut-brain relationship with relevance for future (pre-)clinical research. As the gut represents a unique, minimally invasive window to assess neuropathology, our work may spark the development of early biomarkers that directly report on disease progression in AD-patients. Moreover, confirming the notion that microbial-derived amyloids could represent a putative trigger for pathology may cause a paradigm shift for AD therapy."

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    • Research Project

    Madmaps. Multimodel whole-brain staging in tauopathy mouse models. 01/01/2018 - 31/12/2019

    Abstract

    Despite being the most prevalent form of dementia in the world, there still is no cure for Alzheimer's disease (AD). A breakthrough in the development of therapies can only be achieved by generating new insights in the mechanisms that underlie disease development. Although it has become clear that AD is characterized by the progressive accumulation of aberrant proteins in the brain, it is not yet known to what extent their spread correlates with detrimental cellular effects, such as the loss of neuronal connections. This requires an integrated approach that can grasp the functional and structural changes with high resolution in the intact brain through time. No such technology exists as yet. That is why we will combine two sophisticated whole-brain imaging technologies to follow up a well-characterized mouse model for AD during different stages of the disease. Whilst alive, we will monitor brain function - specifically, the connections between brain regions - using an advanced MRI-based technique. Then, we will visualize the structure of the exact same brains at the cellular level using a newly developed microscopy technique that relies on rendering tissue optically transparent. The combination of both into multimodal AD brain maps (or briefly, MADMAPS) will provide unprecedented detail in the neurodegenerative process and allow for correlating functional changes with microscopic defects. On the longer term, the same approach will enhance the reproducibility and reliability of preclinical therapeutic studies by enabling distribution analyses and efficacy tests of disease-modifying compounds.

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    Purchase scanning electron microscope 01/01/2018 - 31/12/2018

    Abstract

    This project comprises the purchase of a new scanning electron microscope for studying surface features of biomedical samples and replaces the SEM515 (purchased in 1987). The new instrument allows examination of samples both at low and high vacuum conditions.

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    Unraveling the potential of circular RNAs as novel biomarkers of radiation exposure and- sensitivity and their functional characterization in the radiation response 15/10/2017 - 14/10/2021

    Abstract

    Biomarkers for radiation exposure are important for a number of reasons. With a growing nuclear threat, the identification of efficient biomarkers for radiation exposure that enable fast triage of exposed individuals is becoming increasingly important. Likewise, the identification of robust biomarkers of radiosensitivity should help tuning current tumor radiotherapies to more personalized schemes. Current golden standard methods for biodosimetry such as cytogenetics assays fall short in several aspects related to emergencies, in that their analysis is very laborious, time-consuming and expensive and therefore not amenable for fast screening of large cohorts. In the last decade, gene expression signatures have emerged as potential biomarkers that could be useful for the abovementioned purposes1–6. We have recently taken this research a step further with the identification of exon expression signatures as robust radiation biomarkers7 which are more sensitive than gene signatures, and therefore more suitable in the case of low-dose exposures. One of the main disadvantages of classical mRNA biomarkers is their inherent instability. Circular RNAs (circRNAs) are a recently described class of non-coding RNA molecules9,10, of which the expression varies according to the cell/tissue-type and developmental timing11–16. Due to their covalently closed circular structure, circRNAs are resistant to exonuclease degradation, and therefore remarkably stable17. This, together with observations that circRNAs are highly abundant in blood cells18 and furthermore enriched in exosomes from human serum19 gives them a very high potential as biomarkers in general, and radiation biomarkers in particular. Hence, in this PhD project, we will identify circRNA biomarkers for radiation exposure and radiosensitivity and characterize the functions of the most promising ones.

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    Short circuits in the neuronal network. A role for B-type lamins? 01/10/2017 - 30/09/2019

    Abstract

    Long-term adaptations of the brain, such as memory formation, rely on a delicate dialogue between neurons that is typified by intensive remodeling of both cellular and nuclear morphology. Recent observations suggest an important role for B-type lamins in neurodevelopment. We suspect that lamins interfere with neuronal plasticity via their architectural function in the nucleus. However, the exact mechanisms remain to be determined. Using a combined strategy of molecular profiling and deep imaging approaches, we aim at exposing a novel link between lamins and neuronal function. This way, we intend to further our understanding of a new phenotypical branch in the rapidly expanding tree of laminopathies and identify potential novel biomarkers or drug targets with relevance for the even larger spectrum of neurodevelopmental disorders.

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    • Research Project

    Border control: Exposing the molecular mechanisms of nuclear envelope rupture and repair 01/10/2017 - 30/09/2019

    Abstract

    The nuclear lamina is a critical regulator of nuclear structure and function. Defects in its major constituent proteins, A-type lamins, cause diseases known as laminopathies. Our group has discovered that laminopathy cells experience transient ruptures of the nuclear envelope, leading to illegitimate exchange of proteins between the cytoplasm and the nucleus. This feature contributes significantly to disease development in laminopathies, but also plays a key role in cancer. However, little is known about the underlying mechanisms. Considering its medical potential, we want to pinpoint the drivers of rupture induction and repair in a systematic manner. Using a combined strategy of molecular profiling and deep coverage microscopy we will further our understanding of the rapidly expanding tree of laminopathies, and may expose new therapeutic entry points with relevance for an even broader spectrum of lamin-associated disorders.

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    The study of the possible interactions between human Mas-related G Protein-coupled receptors. 15/07/2017 - 14/07/2018

    Abstract

    Mas-related G-Protein coupled receptors (Mrgpr's) have a putative role in sensory processes, including itch and pain. Previous studies on Mrgpr's in intestinal inflammatory conditions revealed marked expressional changes in them, specifically in sensory neurons of enteric nervous system (ENS). The fact that most of Mrgpr's are still classified as orphan, has hampered the study of their functions and regulatory mechanisms. This project develops novel approaches to explore the function of Mrgpr despite their current orphan status and explores protease-linked activation mechanisms of these Mrgprs. MrgprE and MrgprF are of special interest since these receptors are co-expressed in both enteric plexusses (myenteric and submucosal), and co-regulated in Schistosoma mansoni and TNBS-induced ileitis murine models. Mouse and human MrgprE and MrgprF are orthologous, and ongoing studies on gut biopsies in our laboratory confirm expression of MrgprE and MrgprF in the human gastrointestinal tract. This has prompted us to elucitade the interaction of human (h-) MrgprE and MrgprF. Therefore, we employed various biophysical and biochemical techniques including a novel luciferase complementation technique (NanoBiT), Bioluminescence resonance energy transfer (BRET), Fluorescence resonance energy transfer (FRET) and co-immunoprecipitation to validate our hypothesis. Results gave concrete evidence of h-MrgprE/h-MrgprF heteromerization, as well as h-MrgprE and h-MrgprF homomerization respectively. Over the last decade examples of GPCR's homo- and hetero-merizations are increasing at accelerating pace. Homo- and heteromeric states of GPCR's modulate the signal transductions capabilities and, therefore, regulate G-protein-dependent or -independent signalling associated with them. Nevertheless, biophysical tools used for detecting homo- and heteromerization of GPCR's account only for the oligomerization state but do not define their affinity and the competition among interacting partners for oligomerization. Therefore, there is need of novel protein-protein interaction (PPI) tools to ascertain affinity and competition among GPCR's. Starting from our obtained results, we are developing a quantitative NanoBiT assay, which will expand the current PPI tools and provide a better tool to study affinity, competition, biased agonism and transient protein interactions.

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    Synpases in Action: From high-throughput fluorescence imaging assays of synaptic function to drug discovery. 01/07/2017 - 31/03/2020

    Abstract

    This project aims at developing and implementing novel optogenetic tools and genetically-encoded reporters of synaptic activity in combination with computational tools to quantitatively assess synaptic function. This way, we will establish a next-generation of in vitro high-throughput assays to study the effects of neuropathology on synaptic function and also to screen for novel disease-modifying molecules.

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    Whole-brain microscopic imaging in the intact neurodegenerative brain. 01/01/2017 - 31/12/2017

    Abstract

    Many neurodegenerative diseases are typified by molecular infectivity, with aggregates spreading through interconnected neuronal networks. As yet, it is not clear how such pathological aggregates spread beyond the initial sites of impairment and how this correlates with local neurodegenerative features, such as the onset of neuroinflammation and associated synaptic and neuronal loss. Monitoring the spatiotemporal spreading pattern of pathological aggregates and associated neurodegenerative features requires a methodology for accurately following up the evolution of disease manifestations within the brain, and this with cellular detail. To this end, we intend to optimise and exploit a nondestructive, high-resolution microscopic imaging approach, based on chemical clearing and light sheet microscopy, to visualise the intact neurodegenerative brain.

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    Adeno-associated viral vectors in neurogastroenterology: a novel versatile preclinical toolbox and a first step towards gene therapy. 01/01/2017 - 15/12/2017

    Abstract

    The enteric nervous system (ENS) is an extensive nervous system in the gut wall that governs crucial gastrointestinal functions including motility, secretion and blood supply. Furthermore, the ENS interacts with the immune system to keep a delicate balance between fending of pathogens and keeping tolerance towards unharmful microbiota. Defects in the ENS can lead to potentially fatal diseases such as Hirschsprung's disease, in which a failure of ENS development leads to severe constipation in newborns. Subtler defects in ENS functioning can lead to functional bowel diseases, often associated with motility disorders. To study the impact of specific proteins or genes in these diseases, the generation and breeding of genetically altered animals is often required. This is time- consuming, labor-intensive and expensive. Moreover, ethical concerns may rise if the genetic alteration leads to breeding of permanently diseased animals. This project investigates the validity of adeno-associated viral vectors (AAV) as a tool to genetically alter cell types of interest, or specifically label them for advanced microscopical evaluation. AAV have shown proven merit in research in the central nervous system, but have been undervalued in the domain of neurogastroenterology. This project develops strategies in which AAV can be used not only to investigate genetic defects, but also to correct them, which is a necessary basis for (individualized) gene therapy approaches in ENS disorders.

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      • Research Project

      Border control: getting a grip on nuclear envelope rupture and repair. 01/10/2016 - 30/09/2017

      Abstract

      The nuclear lamina is a critical regulator of nuclear structure and function. Defects in its major protein constituents, the A-type lamins, cause a spectrum of diseases referred to as laminopathies. We have discovered that laminopathy patient cells repetitively experience transient ruptures of the nuclear envelope, leading to illegitimate exchange of proteins between the cytoplasm and the nucleus. This feature contributes significantly to disease development in laminopathies, and may also play an important role in aging and cancer. However, as yet, little is known about the underlying mechanisms. Using a combined strategy of molecular profiling and deep imaging, we aim at unveiling the major pathways that govern nuclear compartmentalization. This way, we intend to further our understanding of the rapidly expanding tree of laminopathies, and identify new therapeutic entry points with relevance for an even broader spectrum of lamin-related disorders.

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      SKiN-HUID 01/09/2016 - 31/08/2019

      Abstract

      This is an Interreg Vlaanderen-Nederland project, so the project language is Dutch. This way, no English abstract is available. Kanker is één van de meest bedreigende ziekten van deze eeuw met jaarlijks wereldwijd 8 miljoen doden. De complexiteit van kanker maakt dat deze ziekte enkel succesvol behandeld kan worden door innovatie en vertaling van kennis naar nieuwe geneesmiddelen en behandelingsstrategieën. Onder leiding van Universiteit Maastricht streven Universiteit Antwerpen, VIB, Basic Pharma Technologies, and MosaMedix ernaar een antwoord te bieden op de specifieke uitdagingen van huidkanker. Dit consortium wordt financiëel ondersteund door het Interreg V programma van Interreg Vlaanderen-Nederland en EFRO (Europees Fonds voor Regionale Ontwikkeling). SKiN-HUID is een grensoverschrijdend project dat een unieke behandeling van huidkanker ontwikkelt op basis van een Anx-A5 gebaseerd platform voor 'Target Drug Delivery'. Het omvat een gerichte toediening van medicijnen via elektrische of hyperthermische stimulatie die stress op de cellen zet. Voordelen van deze techniek zijn het efficiënt en doelgericht inkoppelen van toxische farmaceutische hoeveelheden, maar op basis van een verminderde dosis zodat algemene bijwerkingen beperkt blijven en de levenskwaliteit van de patiënt gehandhaafd blijft. De bedoeling is om deze technologie binnen 'SKiN-HUID' verder uit te spinnen tot een therapie, via preklinische en klinische validatie. Het VIB-labo van Prof. Chris Marine (KULeuven) voorziet hierin van wereldexpertise betreffende huidkanker en meer bepaald melanomas. Het labo waarvan Prof. John-Paul Bogers (UAntwerpen) deel uitmaakt, heeft een sleutelrol in biomedische microscopie en toxicologische analyse van proefdoermodellen. Tevens nemen zij een leidende rol op in het hyperthermie onderzoek. Met het labo van Prof. Chris Reutelingsperger (UMaastricht) heeft het project toegang tot unieke expertise en biochemische technologie over annexine. De Basic Pharma groep levert expertise en de faciliteiten voor de ontwikkeling van GMP productie en farmaceutische formuleringen, in samenwerking met MosaMedix, wat bijdraagt met zijn Annexine-technologie platform.

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      Modular confocal microscopy platform with light sheet illumination. 01/05/2016 - 30/04/2020

      Abstract

      The application concerns an innovative microscopy platform for visualizing cells, tissue specimen and living small model organisms in three dimensions at unprecedented speed and with excellent resolution and contrast. As a unique feature, the platform is equipped with a light-sheet module, which is based on an orthogonal configuration of laser-generated, micrometer-thin plane illumination and sensitive one-shot detection. Seamless integration with confocal modalities enables imaging the same sample from the micro- to the mesoscale. The device has a broad application radius in the neurosciences domain inter alia for studying neurodegeneration and -regeneration (e.g. whole brain imaging, optogenetics); but it also has direct utility in various other fields such as cardiovascular research (e.g. plaque formation and stability), plant developmental research (e.g. protein localization during plant growth) and ecotoxicology (e.g. teratogenicity and developmental defects in zebrafish). Furthermore, its modular construction will enable adaptation and targeted expansion for future imaging needs.

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      Prenatal adeno-associated viral transduction of the enteric nervous system as a novel toolbox in neurogastroenterological research. 01/04/2016 - 31/03/2017

      Abstract

      The enteric nervous system (ENS) is responsible for the regulation of basic gastrointestinal functions and harbors different subtypes of neurons, difficult to identify in (live cell) experiments. This research project studies the prenatal transduction of the ENS with recombinant adeno-associated viral vectors with the goal of employing this methodology for the identification, modulation and imaging of functional neuronal subtypes during the development of the ENS.

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        Drug resistance in MYC/MYCN driven tumor entities as a consequence of replicative stress induced DNA damage response : an entry point for synthetic lethal drugs. 01/01/2016 - 31/12/2019

        Abstract

        Chemoresistance is a major impediment to succesful treatment of a growing number of cancer entitites. Circumventing this phenomenon demands highly selective and efficient targeting of cancer-specific pathways. We have recently discovered that MYC(N)-driven tumors show strong upregulation of genes involved in replicative stress-induced DNA damage repair. We thereby identified FOXM1 as a central regulator. Our data suggest that FOXM1 driven DDR is an important determinant in the acquired drug resistance program. In this project we aim at confirming the pivotal role of FOXM1 in drug resistance and dissecting its pathway by integrating knowledge from molecular data sets from patients, primary cell cultures and zebrafish models. This way, we expect to identify novel targets for therapeutic intervention of aggressive or resistant tumors. Once we have established the most vulnerable targets, we will resort to semi-high-throughput screens for pinpointing the most suitable compounds. Subsequently, focused testing of drug combinations on model organisms will prove their in vivo performance and should result in the inclusion of the optimal formulation in phase I clinical trials on patients with highly resistant tumors. Thus, the goal of this project is to devise new and less toxic therapeutic strategies for more efficient killing of tumors and for use in patients in which conventional methods no longer show effect. We thereby consider different MYC(N)- driven tumor types such as neuroblastoma, medulloblastoma, T-cel acute lymphoblastic leukemia and Burkitt lymphoma, emphasising the translational value of our findings.

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        Development of therapeutic strategies against Pseudomonas aeruginosa related VAP. 01/01/2016 - 31/12/2019

        Abstract

        This project represents a formal research agreement between UA and on the other hand IWT/FWO. UA provides IWT/FWO research results mentioned in the title of the project under the conditions as stipulated in this contract.

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        Short circuits in the neuronal network. A role for b type Lamins? 01/10/2015 - 30/09/2017

        Abstract

        Long-term adaptations of the brain, such as memory formation, rely on a delicate dialogue between neurons that is typified by intensive remodeling of both cellular and nuclear morphology. Recent observations suggest an important role for B-type lamins in neurodevelopment. We suspect that lamins interfere with neuronal plasticity via their architectural function in the nucleus. However, the exact mechanisms remain to be determined. Using a combined strategy of molecular profiling and deep imaging approaches, we aim at exposing a novel link between lamins and neuronal function. This way, we intend to further our understanding of a new phenotypical branch in the rapidly expanding tree of laminopathies and identify potential novel biomarkers or drug targets with relevance for the even larger spectrum of neurodevelopmental disorders.

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        • Research Project

        Strengthening the (Sub-Saharan) HPV research network within the African region (WAKA-HPV) taking VLIR-UOS collaborations and the SMU HPV reference centre as a step stone. 01/09/2015 - 31/12/2016

        Abstract

        This project builds upon a successful previous NSS project. The project aims to standardize and focus all HPV related research projects funded through VLIR-UOS in the African region and to look for synergy with HPV projects from other funders and industry. A platform website will share Standard Operating Procedures (SOP's), GCP, standardized survey protocols,… This North South South proposal wants to continue and strengthen the linkage between the interested researchers and participating VLIR-UOS collaborations.

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        High throughput microscopy. 01/06/2015 - 31/12/2016

        Abstract

        In the framework of this project, a method will be established for automated and standardized microscopic evaluation of large numbers of biological samples. Protocols will be tailored for histological tissue preparations and for cell cultures. To this end, a combination of optics, robotics and bio-image informatics will be used.

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        From pictures to numbers : Adding Througput and Readout to Imaging in AD diagnostics (TRIAD). 01/05/2015 - 31/10/2017

        Abstract

        This project represents a formal research agreement between UA and on the other hand the client. UA provides the client research results mentioned in the title of the project under the conditions as stipulated in this contract.

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        Expression and role of dipeptidyl peptidases and related peptidases in acute lung injury. 01/01/2015 - 31/12/2018

        Abstract

        Acute lung injury remains the third major cause of mortality worldwide, and it is assumed that excessive inflammatory responses could be involved. The precise role of dipeptidyl peptidases (DPPs; a family of enzymes that cleave off dipeptides from the amino terminus of peptides) in the pathophysiology of acute lung injury is poorly understood. Taken broadly, the DPP family consists of DPPIV, fibroblast activation protein alpha (FAP), prolyl oligopeptidase (PREP), DPP8 and DPP9. DPPIV inhibitors are used in the treatment of diabetes type 2, but evidence for other roles of DPPIV is also emerging. Despite a presumed role of individual peptidases in lung disease, knowledge on DPPs in acute lung injury remains limited. Previously, we have shown that DPPIV inhibitors protect against lung ischemia-reperfusion induced injury. Apart from that, we discovered that DPP9 has a role in macrophage activation, which is an important component of acute lung injury. The current project aims to explore the hypothesis that DPPIV, DPP9 and related peptidases play a role in the pathophysiology of acute lung injury. We will study the expression of DPPs in both an infectious and a non-infectious mouse model of acute lung injury. Subsequently, we will determine the effect of DPPIV inhibition on the outcome, and will assess whether DPPs have a role in lung macrophages. We will compare the animal findings with measurements in human tissue to study the translational potential of our results.

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        Targeted drug delivery for cancer treatment, in-vitro proof of principle for malignant melanoma. 01/01/2015 - 30/06/2016

        Abstract

        The PoC project validates the proposed target drug delivery mechanism for malignant melanoma and foresees in-vitro tests for the validation and verification of the different steps in the drug delivery mechanism. The project objective is the definition of an in vitro validated protocol for the complete chain of the drug delivery mechanism for malignant melanoma.

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        Unveiling the role of nuclear compartmentalisation in laminopathies with intelligent high content imaging and spatial proteomics. 01/10/2014 - 30/09/2018

        Abstract

        Laminopathies are orphan diseases caused by mutations in the LMNA gene, which encodes A-type lamins. Recent evidence suggests that lamin defects cause abnormal nucleocytoplasmic compartmentalization. This feature is prone to contribute significantly to disease development in laminopathies, and may also play an important role in aging and certain cancers. With an eye on its medical potential, we want to expose the exact underpinnings of defective compartmentalization.

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        Clarity in the clouded brain, establishing spatiotemporal fingerprints of neurodegeneration using whole brain imaging. 30/09/2014 - 31/12/2019

        Abstract

        The aim of this project is to establish a method for mapping neurodegenerative processes in mouse models, using a combination of tissue clearing, advanced fluorescence microscopy and image processing. This project represents a formal research agreement between UA and on the other hand IWT. UA provides the IWT research results under the conditions stipulated in this contract.

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        Light sheet microscopy. 01/09/2014 - 31/08/2017

        Abstract

        In this project, we will establish and benchmark a whole-brain imaging approach to monitor spreading of neurodegenerative protein aggregates; in other words, we wish to establish 4D reference maps of neurodegenerative pathologies. To this end, we will combine state-of-the-art tissue clearing strategies with advanced light microscopy and image informatics.

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        Short circuits in the neuronal network, a novel role for lamins? 01/02/2014 - 31/12/2014

        Abstract

        Neuronal communication depends on remodelling of cellular and nuclear morphology. Lamins, architectural proteins of the nucleus, have recently been implicated in neurodevelopmental disorders. To uncover their role in neuronal (dys-) function, we will monitor in vitro neuronal networks upon chemical or genetic perturbation of lamins, by exploiting high-content morphological analyses and live cell calcium imaging.

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        Mas-related gene receptors as new mediators of gastrointestinal neuro-immune communication. 01/01/2014 - 31/12/2017

        Abstract

        The current project aims to further explore the role and regulation of Mrgs in the gastrointestinal tract. We will study the function of Mrg in neurons and mast cells using advanced microscopical and cell biological techniques. Furthermore we plan to explore the role of Mrg beyond inflammatory intestinal pathologies, i.e. to investigate the involvement of these receptors in irritable bowel syndrome. We will combine animal models with research in human tissues to study the translational potential of the findings. Ultimately, this study aims to provide insight in the role of Mrg receptors in gastrointestinal pathologies.

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        Red meat and colorectal cancer. 01/01/2014 - 31/01/2017

        Abstract

        Colorectal cancer (CRC) is one of the most lethal cancer types in the world. The major culprit in CRC development is considered to be the Western diet; the consumption of red and processed meat gaining particular attention in this context. To assess the potentially adverse effects of meat uptake we propose a cytometric strategy, based on a multiparametric cyto- and genotoxicity analysis of colon cell cultures that are incubated with in vitro digested meat extracts. Using a top-down approach, we will systematically compare the impact of different meat types on cell viability, morphology, stress and DNA damage in cell monolayers, as well as more complex, but physiologically more relevant cellular models, such as differentiated and 3D cell cultures. Finally, using this setup, we will assess the potentially beneficial impact of co-administrating specific antioxidants or food extracts. The proposed research will provide fundamental insights in the causal relationship of red meat consumption and CRC development and give the first clues towards potential countermeasures. This will provide nutrition community with valuable information to refine their recommendations on red meat consumption, and help the meat industry in tuning their production and processing protocols.

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        Elucidating the role of progranulin in neuroneural and systemic inflammation in a novel mouse model. 01/01/2014 - 31/12/2014

        Abstract

        The results achieved with this study will be instructive in the understanding of the complex GRN biology, especially in the elucidation of the role of age-related neuroinflammation, and would lead to the development of key molecular targets involved in GRN-related diseases.

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        Set up of HPV reference centre and establishment of HPV research network within the African. 13/12/2013 - 31/05/2015

        Abstract

        HPV is the main, almost unique cause of cervix carcinoma in adult women. Unfortunately, currently, many African countries lack comprehensive data on the circulating HPV types and Africa may harbor a variety of unexplored circulating HPV types which are uniquely distributed in various cancers and benign lesions. This NSS initiative will establish a HPV research network between several VLIR partners of whom some are already conducting HPV and/or cervix carcinoma research with own VLIR-UOS funding.

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        • Research Project

        Research in the field of the advanced biomedical microscopic imaging: "Towards medical cytomics. Paving the way with nextgeneration microscopy". 01/10/2013 - 30/09/2018

        Abstract

        The techniques for monitoring and manipulating cells have reached a level of maturity that allows them to be implemented in high-level biological research. The promotor wants to grasp this momentum and raise the standard in modern microscopy technology while connecting cellular phenotypes with disease development. From a biological perspective, it is the goal to elucidate the mechanisms underlying cellular dysfunction in the context of genetic diseases, termed laminopathies. This research field is of particular importance because these pathologies show highly diverse manifestations and they magnify features of widespread degenerative processes like human aging. At the cellular level, all laminopathies demonstrate problems with the nuclear lamina, a structure that physically supports the cell nucleus.

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        • Research Project

        Electrical excitation in cancer therapy for the reduction of undesired side-effects (ELEKTRON). 16/09/2013 - 15/01/2015

        Abstract

        This project represents a formal research agreement between UA and on the other hand Universiteit Maastricht. UA provides de Universiteit Maastricht RC research results mentioned in the title of the project under the conditions as stipulated in this contract.

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        • Research Project

        From mice to men and back. Human iPSC-derived neurons to boost Drug Discovery in Alzheimer's disease (DDIPS). 01/04/2013 - 31/03/2015

        Abstract

        This project represents a formal research agreement between UA and on the other hand private institution. UA provides private institution research results mentioned in the title of the project under the conditions as stipulated in this contract.

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        • Research Project

        Are mas-related gene receptors involved in irritable bowel syndrome? 01/02/2013 - 31/12/2013

        Abstract

        Mas-related gene receptors (Mrg) form a family of G-protein coupled receptors that has been implicated in nociception and mast cell activation. Previous work from our research group points towards a strong plasticity and role of the Mrg receptor family in intestinal inflammation. We now want to explore whether expressional changes of the Mrg receptor family are specific to inflammatory bowel disorders or also occur in irritable bowel syndrome (IBS). One of the presumed pathogenesis mechanisms for IBS is a perturbed neuro-immune interaction between neurons and mast cells, the two cell types that mainly express Mrg receptors. We will follow two parallel research paths. Firstly, we will employ a maternal separation stress model in mice, known to induce visceral hypersensitivity, as an animal model for IBS. Secondly, we will study human biopsy material from IBS patients versus healthy controls. In both the animal and the human study, we will examine Mrg expression using quantitative PCR and immunohistochemical techniques. This strategy will on one hand allow us to evaluate the translational possibilities of the animal model, given that there are some differences between Mrg receptors in mice and human, and on the other hand for the first time shed light on the expression of Mrg receptors in IBS. The fundamental research project at hand will allow us to ascertain if Mrg receptors are valuable targets in therapy or diagnosis and forms a basis for further functional studies.

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          • Research Project

          Evidence-based medicine in cancer prevention at the University of Antwerp. 01/10/2012 - 30/09/2014

          Abstract

          The goal of this project would be the creation of a workgroup which would 1) investigate the knowledge and expertise which is already available within the University of Antwerp (faculty of medicine) regarding evidence-based medicine and systematic reviews/meta-analyses/Cochrane reviews; 2) training and support of candidate systematic reviewers in the field of cancer prevention; 3) to collaborate in the Cochrane review group and 4) to develop and promote activities of evidence-based cancer prevention throughout the University which could result, in the future, in the creation of the Cochrane field on cancer prevention.

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          • Research Project

          Elucidation of host-pathogen interactions in a rodent model of pneumonia. 01/01/2012 - 31/12/2015

          Abstract

          Ventilator associated pneumonia is a major cause of mortality and morbidity in hospitalized patients. To study the etiopathogenesis of this disease, rodent pneumonia models will be developed and characterized using histopathology, microbiology, transciptomics and proteomics from both host and bacterium. Possible distinct pathogenic steps will be validated in human patient samples.

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          • Research Project

          Role of human papillomavirus infection and other co-factors in the aetiology of head and neck cancer in India and Europe (HPV-AHEAD). 01/09/2011 - 31/08/2015

          Abstract

          Human papillomavirus (HPV) is responsible for approximately 25% of head and neck cancer (HNC) worldwide and appears to be associated with a better response to treatment and improved prognosis. Evidence suggests that HPV-induced HNC has steadily increased in the USA and some European countries in the last decades. However, whether this is a worldwide phenomenon and specific risk factors are associated with it remains to be proven. In addition, little is known on the natural history and risk factors of oral HPV infection. HPV-AHEAD network aims to address these and other unanswered questions on HNC etiology and epidemiology with a focus on the role of HPV.

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          • Research Project

          Neuropatholgical image analyses in Alzheimer's disease mouse models treated with anti-amyloidotic and vasogenic compounds 01/07/2011 - 31/12/2015

          Abstract

          The varied morphological and biochemical forms in which Aβ deposits in brain of Alzheimer's disease (AD) patients are complex and the mechanisms that drive their formation are not yet properly understood. Aβ is predominantly deposited in brain as dense-core and diffuse plaques and in cerebral vascular walls. The dense-core plaques and vascular amyloid, but not diffuse plaques, are associated with tau pathological changes in the surrounding brain tissue, suggesting that such amyloid deposits are toxic, although structural changes associated with diffuse plaques have not yet been studied in detail. Mutations in amyloid precursor protein or presenilin genes cause an increased production of Aβ42 compared to the more physiological and soluble Aβ40 isoform. However, in the majority of AD patients, no known cause is identified and is postulated to be due to failure of Aβ clearance or other mechanisms. Nevertheless, mutations identified in familial AD have allowed development of a number of mouse models that mimic most of the pathological features of AD and have been highly instrumental in furthering our understanding of different aspects of AD neuropathology. These mouse models are also being extensively utilized for testing drugs, in what we call as preclinical mouse trials. These mice are eventually evaluated for drug efficacy based on reversion of behavioural and cognitive abilities, however, these methods are cumbersome and time-consuming and not useful in the high-throughput first screens. For drugs that target Aβ, reduction of plaque load is a good indicator of drug efficacy, but an increasing number of drug candidates do not target Aβ directly. Thus, biomarkers including those based on histopathology, as AD is definitively diagnosed on neuropathology, are urgently needed in the field. As a part of an international consortium, we had earlier identified an important association of a subset of amyloid plaques (namely, dense core plaques) with vessel walls (Kumar-Singh et al., 2005). Importantly, structural microvascular defects were also identified not only in amyloidogenic vessels but also in non-amyloidogenic vessels, suggesting a key role of vessels in the etiopathogenesis of AD (Kumar-Singh et al., 2005). However, structural microvascular defects were most robustly identified only on electron microscopy, a technique that is cumbersome and time-consuming, and therefore again not suitable for routine analysis in mouse preclinical trials. To test the feasibility of a faster approach, we employed tissue fractal dimension image analysis on two AD mouse models and compared them with AD patients and aged controls. We showed that the various types of plaques present in humans and transgenic mice have comparable fractal dimensions that also accurately differentiated various types of plaques in both species. These data not only suggest that mouse models reproduce plaque pathology present in AD, but also that image analysis could be a valuable tool for objective, computer-oriented diagnosis of AD-associated changes. The project aims to extend these studies in larger series and also intends to quantify parenchymal and especially vascular parameters. The identified image analysis parameters would also be evaluated for reversion to normal values in mice treated with Aβ-clearing and vasoactive compounds. A successful outcome of this project promises to deliver early amyloidotic and non-amyloid markers that will not only provide diagnostic tissue image parameters for high-throughput drug screening in mouse models, but will also give important insights into AD etiopathogenesis.

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          • Research Project

          Study of the proportion of pulmonary neuro-epithelial bodies in vagal reflex activities based on stimuli in the respiratory tracts. 01/01/2011 - 31/12/2012

          Abstract

          This project represents a research agreement between the UA and on the onther hand IWT. UA provides IWT research results mentioned in the title of the project under the conditions as stipulated in this contract.

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          • Research Project

          Identification of functional molecular pathways in the pulmonary neuroepithelial body micro-environment: an initial gene expression analysis 01/01/2011 - 31/12/2012

          Abstract

          A 'whole mouse genome microarray' analysis will be performed to compare the gene expression patterns of pulmonary neuroepithelial bodies (NEBs) and control airway epithelium. This approach may characterise ion channels, molecular receptors and signalling transduction pathways that make the NEB micro-environment unique. The 'unbiased' approach should allow for more focussed functional studies of these complex sensory airway receptors.

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          • Research Project

          Identification of functional molecular pathways in the pulmonary neuroepithelial body microenvironment: Laser capture microdissection and gene expression study. 01/01/2011 - 31/12/2011

          Abstract

          This project aims at identifying pathways that are involved in the normal function of NEBs in postnatal lungs. The NEB microenvironment will be dissected in large numbers via advanced laser capture microdissection and will be used for gene expression analysis.

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          • Research Project

          Live cell imaging of phosphatidylserine-annexin A5-mediated pinocytosis: study of targeted drug delivery for cervical cancer 01/01/2011 - 30/11/2011

          Abstract

          Targeted drug delivery requires targeting agents that guide therapeutic compounds to the diseased lesion. Annexin A5 (anxA5) binds with high affinity to membranes bearing phosphatidylserine (PS) and opens a portal for cell entry. This PS-anxA5-mediated pinocytic pathway has been described for cells undergoing apoptosis and in tumour cells. PS is also exposed on the cell surface of virus-infected cells and endothelial cells of tumour blood vessels. Therefore, anxA5 coupled to drugs may be a useful tool in anti-cancer or anti-virus therapy. This study aims to get a better insight into the cell entry and intracellular processing of anxA5. Live cell imaging techniques will be used for the real-time tracking of anxA5 in several cell lines. In the context of the human papillomavirus-induced cervical carcinogenesis, this study will determine whether viral infection and/or neoplasia are essential for anxA5 internalisation, and will try to identify the specific circumstances of PS exposure and cell entry. Additionally, the effect of the conjugation of therapeutic molecules to anxA5 on cell entry, subcellular trafficking and cell viability will be evaluated.

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            • Research Project

            Putative noxious effects of the insecticide deltamethrin on the enteric nervous system in mammals. 01/08/2010 - 31/05/2011

            Abstract

            The insecticide deltamethrin, a powerful synthetic pyrethroid, acts toward insects by ingestion or contact, altering normal neuronal function. Deltamethrin is known to modify sodium channel activities and intracellular calcium concentrations in neurons. It is of moderately high toxicity in mammals. Deltamethrin will increasingly be used in agriculture, resulting in an increased exposure of man to deltamethrin in time. This project focuses on the effects of the prolonged oral congestion of non-toxic doses of deltamethrin on the intrinsic and extrinsic innervation of the mammalian gastrointestinal tract. The study comprises morphological (multiple immunofluorescence and in situ hybridisation techniques) and microscopic (fluorescence or confocal laser scanning microscopy) techniques to detect effects of deltamethrin on viability and chemical coding of neurons in the gastrointestinal tract and in spinal and nodose ganglia of mouse and rat. Quantitative RT-PCR will be used to verify whether semi-quantitative changes occur at the mRNA level. Cultures of isolated vagal, spinal or enteric neurons will be applied to study in vitro the effects of deltamethrin in time on neurons using classic intracellular electrophysiological recording and optical recording. The obtained data will be helpful to recognize, prevent and treat putative noxious effects of a prolonged exposure to non-toxic doses of deltamethrin.

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            • Research Project

            CLCI - High end infrastructure for confocal live cell imaging. 22/07/2010 - 28/04/2015

            Abstract

            This project represents a formal research agreement between UA and on the other hand the Flemish Public Service. UA provides the Flemish Public Service research results mentioned in the title of the project under the conditions as stipulated in this contract.

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            • Research Project

            Characterizing the effects of inhaled particulate matter on airways: an overall study design from atmosphere to alveoli. 01/12/2009 - 30/11/2010

            Abstract

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            • Research Project

            Neuronal networks in vitro: spontaneous activity and synaptic plasticity in health and disease. 01/10/2009 - 30/09/2013

            Abstract

            This project represents a formal research agreement between UA and on the other hand the Flemish Public Service. UA provides the Flemish Public Service research results mentioned in the title of the project under the conditions as stipulated in this contract.

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            • Research Project

            Euroregional Platform for Advancing Cancer Treatment II 01/04/2009 - 01/04/2012

            Abstract

            This project represents a formal research agreement between UA and on the other hand Interreg. UA provides Interreg research results mentioned in the title of the project under the conditions as stipulated in this contract.

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            • Research Project

            Study of the proportion of pulmonary neuro-epithelial bodies in vagal reflex activities based on stimuli in the respiratory tracts. 01/01/2009 - 31/12/2010

            Abstract

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            Project type(s)

            • Research Project

            Transmission Electron Microscope with cryo-ware. 19/12/2008 - 18/12/2013

            Abstract

            This project represents a research contract awarded by the University of Antwerp. The supervisor provides the Antwerp University research mentioned in the title of the project under the conditions stipulated by the university.

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            • Research Project

            Human papillomavirus infection: interaction with viral internalisation and processing. 01/11/2008 - 31/10/2009

            Abstract

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            • Research Project

            Influence of RNA-interference on cervical carcinoma cells: stimulation of senescence or apoptosis. 01/10/2008 - 30/09/2010

            Abstract

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            • Research Project

            Role of eNOS uncoupling in heart failure. 12/03/2008 - 31/12/2009

            Abstract

            The last years, eNOS-uncoupling became an important new concept in the cardiopathogenesis of myocardial infarction and endothelial dysfunction. Recently, dr. Moens published in two independent Circulation papers the possibility to prevent and reverse eNOS-uncoupling. In this project, the molecular mechanisms of eNOS-uncoupling will be further explored. In addition, the translation will be made to other cardiovascular disorders in which there is evidence of increased oxidative stress as chemotherapy-induced heart failure ind ischemic cardiomyopathy.

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            • Research Project

            The putative effect of corticostatin and neuropeptides belonging to the CRF-family on the interaction between visceral afferents, mast cells and dendritic cells during intestinal inflammation. 01/01/2008 - 31/12/2011

            Abstract

            The aim of this project is (1) to verify whether CRF, UCN2 and UCN3, in addition to UCN1 and CST, also have anti-inflammatory effects on intestinal inflammation; (2) to determine, on the one hand, the effect of these neuropeptides on the neuroimmune interaction during inflammation and, on the other hand, the importance of this effect in the therapeutical effects of these neuropeptides; and (3) to examine which receptors are effectively involved in this process.

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            • Research Project

            Molecular pathological and therapeutic approaches for Alzheimer's disease. 01/01/2008 - 31/12/2011

            Abstract

            Specific aims: -To identify changes occurring in the vascular endothelium or other vascular cellular elements prior to AB deposition as well as to identify novel chaperones from the vascular compartment that facilitate dense core plaque formation. Such studies will greatly aid in identifying novel potential therapeutic targets-i.e., in facilitating therapeutic enhancement of AB clearance or in therapeutically stabilizing or repairing the blood-brain barrier. -To augment the ongoing attempts to therapeutically target clearance of AB from the vascular compartment or increase vascular perfusion by novel approaches or mechanisms.

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            • Research Project

            In situ analysis of the interactions between pulmonary neuroepithelial bodies and a population of stem cell-like airway epithelial cells: a possible link with small cell lung carcinogenesis. 01/01/2008 - 31/12/2011

            Abstract

            For the planned studies, the mouse was chosen as a model, because we have been able to gather for this species a considerable amount of morphological and neurochemical data related to pulmonary NEBs and the associated vCE cells, and of course also because of the additional possibilities that are created for the use of transgenic and knock-out (KO) mouse models. Also, we will be able to use the in situ mouse lung-slice model that was recently developed in our lab (Pintelon et al. 2005), and which will provide unique possibilities for the proposed project via molecular live cdl imaging. Finally, it is interesting to realise that SCLC mouse models (and all other relevant genetic mouse models) can easily be combined with this lung-slice model.

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            • Research Project

            Bidirectional communication between the enteric nervous system and elements of the immune system in inflammatory gastrointestinal disorders. 01/01/2008 - 31/12/2011

            Abstract

            In this project animal models were used to study the interaction between neuronal components of the GI tract and elements of the immune system, more particularly mast cells and dendritic cells, during inflammation. This interaction appears to play an important role in the inflammatory response and might offer a better insight for the observed hyperexcitability of afferent components of the enteric nervous system during gastrointestinal inflammation. This project will primarily focus on the possible role of cortistatin and urocortines in this interaction.

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            • Research Project

            Role of somatostatin and somatostatin receptors in the interaction between mucosal mast cells and enteric neurons during intestinal inflammation. 01/01/2008 - 24/08/2009

            Abstract

            1.Identification and topographical localisation of somatostatin receptors in the enteric nervous system of the non-inflamed mouse ileum using immunohistochemistry and reverse transcriptase-PCR. The somatostatin receptor-containing neurons are neurochemically characterised by means of multiple immunofluerescence stainings. 2.Comparison of the identity and expression pattern of somatostatin receptors in enteric neurons in 8-week Schistosoma mansoni-infected mice with non-inflamed ileum, using Real Time RT-PCR. 3.Optimisation of the protocol for isolation of mucosal mast cells from the lamina propria of 8-week Schistosoma mansoni-infected mice. 4.Identification and quantification of somatostatin receptors on in vitro mucosal mast cells and on mucosal mast cells isolated from the lamina propria of 8-week infected mice by means of immunohistochemistry, reverse transcriptase-PCR and Real Time RT-PCR. These results are substantiated in vivo by immunofluorescent detection of somatostatin receptors on mucosal mast cells in the gastrointestinal tract of Schistosoma mansoni-infected mice. 5.Study of a possible compensatory effect of somatostatin receptor type 2 deficiency on the identity and expression level of the somatostatin receptors in enteric neurons and musocal mast cells using immunohistochemistry, reverse transcriptase PCR and Real Time RT-PCR. 6.Study of the effect of administration of SOM and SOM analogues on the synthesis and secretion of inflammatory mediators by mucosal mast cells using cDNA microarray and ELISA. 7.Functional study of the effect of somatostatin on the neuroimmune interaction between mast cells and enteric neurons using mucosal mast cells and enteric neurons isolated from the gastrointestinal tract of Schistosoma mansoni-infected mice. Life cell imaging and multi-photon microscopy are applied to investigate the activity of both cell types after SOM stimulation.

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            • Research Project

            Elucidating the role of Aß-interacting molecules in the formation of dense-core amyloid placques in association with vessels, and the role of PGRN in frototemporal lobar degeneration. 01/10/2007 - 30/09/2017

            Abstract

            With the help of the key tools of molecular neuropathology ¿ human neuropathology, in vitro cell culture models and transgenic mouse overexpression and knock out models ¿ the project aims to decipher pathways and mechanisms involved in etiopathogenesis of Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD), the two most common causes of presenile dementia. For AD, we are addressing to the mechanism of formation of Aß amyloid that are deposited and are toxic, specifically in relation to fibrillar/nonfibrillar Aß, intracellular/extracellular Aß, Aß40/Aß42, full-length/N-truncated Aß etc. We want to identify molecules that facilitate dense plaque formation at vascular sites as these plaques are the predominant extracellular form of brain Aß deposited in AD patients and mouse AD models. The targets identified here will be exploited for making better mouse models as well as for therapeutic targeting. For the second theme, on FTLD, with the help of mouse and cellular models and human pathological specimens, the project aims to identify molecular mechanism of neurodegeneration. Specifically, progranulin knockout mice, various transgenic mice, and siRNA based cell culture models are being constructed and will be characterized to elucidate whether and how progranulin loss leads to decreased cell survival.

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            • Research Project

            Influence of RNA-interference on cervical carcinoma cells: stimulation of senescence or apoptosis. 01/10/2006 - 30/09/2008

            Abstract

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            • Research Project

            Biomedical microscopic imaging: supporting core facilities 01/05/2006 - 31/12/2021

            Abstract

            This project represents a research contract awarded by the University of Antwerp. The supervisor provides the Antwerp University research mentioned in the title of the project under the conditions stipulated by the university.

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            • Research Project

            Estimation of effectiveness of cervical cancer screening and management of screen-positive women using a population-based case-control study integrated in the Limburg Cancer and Cervical Cytology Registers. 01/04/2006 - 31/03/2009

            Abstract

            In Belgium, in spite of substantial resources, spent in cytological screening, cervical cancer still is a considerable public health problem. The efficacy of screening and the reasons of screening failure are unknown. Population and registry-based case-control studies allow estimating unbiased relative risks of cancer linked with a series of factors. This study aims to assess in 120 women with cervical cancer and in 360 matched controls the following factors: screening history, accuracy of cytological screening, verified by re-screening of retrieved Pap smears of previously screened women, and the follow-up of screen-positive women. Moreover, HPV DNA detection using ultra-sensitive SPF10 PCR and genotyping, applied on archival smears, will provide estimates of the potential reduction in cervical cancer incidence that can be expected from virological screening or future HPV vaccination. The study will take place in Limburg, because of the existence of the LIKAR cancer register, which is linked with a relatively complete cytology register, set up by a network of laboratories.

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            • Research Project

            Influence of nicotine and related molecules on pulmonary neuroepithelial bodies: a new approach using confocal live cell imaging. 01/03/2006 - 31/12/2007

            Abstract

            Direct effects of cholinergic agonists on neuroepithelial bodies (NEBs) in mouse lungs will be studied in an in vitro model using confocal fluorescent live cell imaging. We will try to identify the involved nicotine ACh receptors on NEBs and their complex innervation by pharmacological, physiological and morphological approaches. Long-term effects of nicotine on NEBs will be studied in vitro, using lung-slice cultures, and in vivo, by 'whole-body exposure'.

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            • Research Project

            Role of dystrophin-associated protein complex in contraction of hepatic stellate cells. 01/01/2006 - 31/12/2009

            Abstract

            In normal liver, intrahepatic resistance changes with variations in portal blood flow, thereby keeping porta )ressure within normal limits. In cirrhosis however, both intrahepatic resistance and splanchnic blood flow are ncreased, resulting in portal hypertension. Although structural changes contribute most to the increasec ntrahepatic vascular resistance, it has become clear that not only fixed, but also dynamic factors add significantly the increased resistance. This dynamic part is caused by active contraction of septal and/or portal nyofibroblasts, activated hepatic stellate cells (HSC) and portal venules. Activated HSC contract in response tc rarious vasoactive substances and the cells are currently regarded as target cells for treating porta lypertension. Recent years have seen considerable progress towards understanding the signaling mechanism egulating non-muscle cell contractility. Whereas contraction of smooth muscle cells is governed primarily by Ca2+ signaling contractility of non-muscle cells is principally mediated by Rho signaling. It is not known as yet which of both mechanisms plays a greater role in HSC contractility. However, it has been speculated that, as HSC arE Ictivated and exhibit smooth muscle-like features, Ca2+ signaling becomes more important.

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            • Research Project

            Role of somatostatin and somatostatin receptors in the interaction between mucosal mast cells and enteric neurons during intestinal inflammation. 01/01/2006 - 31/12/2007

            Abstract

            1.Identification and topographical localisation of somatostatin receptors in the enteric nervous system of the non-inflamed mouse ileum using immunohistochemistry and reverse transcriptase-PCR. The somatostatin receptor-containing neurons are neurochemically characterised by means of multiple immunofluerescence stainings. 2.Comparison of the identity and expression pattern of somatostatin receptors in enteric neurons in 8-week Schistosoma mansoni-infected mice with non-inflamed ileum, using Real Time RT-PCR. 3.Optimisation of the protocol for isolation of mucosal mast cells from the lamina propria of 8-week Schistosoma mansoni-infected mice. 4.Identification and quantification of somatostatin receptors on in vitro mucosal mast cells and on mucosal mast cells isolated from the lamina propria of 8-week infected mice by means of immunohistochemistry, reverse transcriptase-PCR and Real Time RT-PCR. These results are substantiated in vivo by immunofluorescent detection of somatostatin receptors on mucosal mast cells in the gastrointestinal tract of Schistosoma mansoni-infected mice. 5.Study of a possible compensatory effect of somatostatin receptor type 2 deficiency on the identity and expression level of the somatostatin receptors in enteric neurons and musocal mast cells using immunohistochemistry, reverse transcriptase PCR and Real Time RT-PCR. 6.Study of the effect of administration of SOM and SOM analogues on the synthesis and secretion of inflammatory mediators by mucosal mast cells using cDNA microarray and ELISA. 7.Functional study of the effect of somatostatin on the neuroimmune interaction between mast cells and enteric neurons using mucosal mast cells and enteric neurons isolated from the gastrointestinal tract of Schistosoma mansoni-infected mice. Life cell imaging and multi-photon microscopy are applied to investigate the activity of both cell types after SOM stimulation.

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            • Research Project

            Internalisation and intracellular transport of HPV in the human cell: study of a functional siRNA knock-out model. 01/01/2006 - 31/12/2007

            Abstract

            HPV is fundamentally important in the carcinogenesis of cervical carcinoma. The initial mechanism of HPV-infection via binding on the cell surface, internalization and cytoplasmic transport has not been entirely elucidated. This study aims to clarify the contradictions concerning the exact endocytosis mechanism of HPVs through an epsin-negative cell line and will investigate the intracellular processing of the virus.

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            • Research Project

            Followed-up of women treated for cervical intra-epithelial neoplasia: prediction of outcomes using HPV DNA testing and molecular markers. 01/01/2006 - 31/12/2006

            Abstract

            The project concerns follow-up after local surgical treatment for high-grade cervical intra-epithelial neoplasia grade 2 or worse. The hypotheses are, that persistence/clearance of HPV DNA in cervical cellular material is an early prognostic marker for cure or relapse after treatment for CIN2+. It allows to shorten follow-up time compared to cytology - colposcopy. Type specific HPV persistence is as sensitive, but more specific than simple presence of HR-HPV DNA determined without type distinction. This can be further detailed by including viral load and a series of molecular progression or proliferation markers. In a case-control design 200 patients will be followed after treatment during 24 months. At several intervals tests will be performed, including new techniques, which may lead to improvement of patient management after treatment.

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            • Research Project

            Influence of RNA interference on cervical cancer : stimulation of senescence and apoptosis. 01/10/2005 - 31/12/2007

            Abstract

            Persistent infection with a high-risk human papillomavirus type (HR-HPV) is a necessary factor in the development of cervical carcinoma. The most important oncoproteins E6 and E7 interfere at crucial points of the cell-cycle. In the present study the technique of RNA interference will be used to reduce the concentration of these 2 oncoproteins. Follow-up of the functional effects will be performed with quantitative and morphological techniques.

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            • Research Project

            Purchase of a spectrophotometer. 13/04/2005 - 31/12/2005

            Abstract

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            • Research Project

            Morpho-functional and neuropharmacological study of neuro-immune interactions in the gastrointestinal tract of the mouse. 01/04/2005 - 31/03/2006

            Abstract

            The aim of this study is the morphological, electrophysiological and neuropharmacological identification of the role, the mechanisms and the effects of the bi-directional interactions between the enteric nervous system and the enteric immune system on the functioning of the gastrointestinal tract under normal and inflammatory conditions.

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            • Research Project

            Study of the mechanisms underlying the immune modulating effects of alcohol within the gastrointestinal tract: involvement of a bidirectional interaction of mast cells and (afferent) neural pathways. 01/01/2005 - 31/12/2006

            Abstract

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            • Research Project

            Study of the mechanisms underlying the immune modulating effects of alcohol within the gastrointestinal tract : involvement of a bidirectional interaction of mast cells and (afferent) neural pathways. 01/01/2005 - 31/12/2006

            Abstract

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            • Research Project

            The neuroimmunologic interaction in Schistosoma mansoni infection. 01/12/2004 - 31/12/2006

            Abstract

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              • Research Project

              Management of low grade squamous intraepithelial lesions (LSIL) in HIV positive patients : effectiveness of cryotherapy and predictors for progression. 01/01/2004 - 31/12/2007

              Abstract

              Study objectives : a) To assess if cryotherapy is more effective* than regular fo\low-up for the management of LSIL in HIV+ women b) I o assess if this effect is different in HIV + than and HIV negative women c) To measure the effect of HIV and HP V (types, shedding, insertion) on regression, persistence and progression of LSIL d) I o measure the effect of cryotherapy on HP V shedding and insertion and on HIV shedding

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              • Research Project

              Fluorescent live cell imaging and CFP/YFP based FRET analysis of the interaction and tetramerization of the subunits of 'silent' ion channels. 01/01/2004 - 31/12/2007

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              Cerebellar function in relation to cortex : models and experiments. 01/01/2004 - 31/12/2007

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              Analysis of neuro-immunie interactions in the small intestine during intestinal schistosomiasis. 01/01/2004 - 31/12/2007

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              Matching fund for the "Research Foundation ¿ Flanders" project "Analysis of neuroimmunologic interactions in the small intestine during intestinal schistosomiasis". 01/10/2003 - 31/12/2007

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              "Calimity fund": replacement of the incubator for light microscopic sections. 01/10/2003 - 31/12/2003

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              The role of molecular markers in the diagnosis of cervical dysplasia. 01/05/2003 - 30/04/2005

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              There is an ongoing evolution to optimise of the primary screening of cervical cancer. Cytology is a labour-intensive method, requiring much expertise and training to reduce interpretative problems to a minimum. Specificity and sensitivity are not optimal. HPV DNA testing is to date to expensive and aspecific to apply in primary screening. Molecular markers are a more specific and physiopathologically interesting alternative.

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              In vitro physiological and functional morphologic study of neurotransmitter receptors related to pulmonary neuroepithelial bodies. 01/05/2003 - 30/04/2005

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              The project should allow us to investigate the presence of neurotransmitter receptors on pulmonary neuroepithelial bodies and their complex selective innervation. Among other methods, we will use our recently developed in vitro lung slice model, which allows the microscopic visualisation of ph~siological parameters by means of the confocal UltraVIEW Live Cell Imager. We plan to concentrate on the neurotransmitters that we previously demonstrated to be present in the system.

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              Effects of proteases, released by mast cells, on afferent pathways in the schistosomiasis inflammation model in the mouse gastrointestinal tract. 01/05/2003 - 30/04/2005

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              PARs are one of the possible sensory oeuron-specific molecular targets that can be useful for therapeutic treatment in inflammatory bowel disorders and gastrointestinal pain. This project aims at elucidating the role{s} of these receptors in the neuroimmune interactions between mast cells and the afferent component of the enteric nervous system in our schistosomiasis inflammation model.

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              Funding for the replacement of basic laboratory equipment intended for the extension of the existing LSM 510 two-photon microscope with the META system. 01/04/2003 - 31/12/2003

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              "Calimity fund": replacement of a defective centrifuge by an Eppendorf 5810R device. 01/03/2003 - 31/12/2003

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              Functional morphological and physiological study of pulmonary neuroepithelial bodies: in vivio and in vitro experimental study of the influence of intermittent hypoxia and of environmental parameters. 01/01/2003 - 31/12/2006

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              Study of the interaction between mast cells and enteric neurons in the ileum of Schistosoma mansoni-infected mice. 01/01/2003 - 31/12/2004

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              In vitro study of the neuro-immune interaction between mucosal mast cells and extrinsic sensory, primary afferent neurons in mice infected with Schistosoma mansoni. 01/01/2003 - 31/12/2004

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              Molecular en functional analysis of novel K+channal subunits identified in the human genome. 01/01/2002 - 31/12/2005

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              Coronary flow after acute myocardial infarction: role of cytokine induced endothelial dysfunction and alfa-adrenergic coronary vascoconstriction. 01/01/2002 - 31/12/2005

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              The role of ghrelin, the recently discovered motilin related peptide, in the regulation of gastric motility in rodents 17/12/2001 - 17/12/2004

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              Research in the field of Biomedical applications of fluorescence microscopic techniques. 01/10/2001 - 30/09/2009

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              "Starting" fund for faculty (ZAP): interdisciplinary research professorship (ZAP-BOF) "Biomedical applications of fluorescence microscopic techniques". 01/10/2001 - 30/09/2004

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              The pulmonary neuroendocrine system in neuronal nitric oxide synthase gene knockout mice. 01/01/2001 - 31/12/2004

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              The proposed functional morphological study of pulmonary NEBs in nNOS gene knockout mice should enable us to evaluate the possibility of a direct involvement of intrinsic pulmonary nitrergic neurons in the peripheral oxygen perception via NEBs. The newest two-photon laser scanning microscope will be used for the microscopical visualisation of physiological reactions of NEBs in vitro

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              Identification and characterisation of genes responsible for hereditary deafness and vestibular dysfunction. 01/01/2001 - 31/12/2004

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              Within the morphological part of this project, the cellular localization and expression pattern of the DFNA5 gene product will be investigated by means of immunocytochemical techniques.

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              Functional morphological study of the interaction between neuronal and non-neuronal elements in relation to oesophageal motility. 01/01/2001 - 31/12/2004

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              The main aims of this project are the study of 1. the correlation between morphological and physiological features of intrinsic esophageal neurons and 2. the role of interstitial cells of Cajal in this part of the gastrointestinal tract.

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              Gastro-intestinal regulatory mechanisms. 01/01/1999 - 31/12/2018

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              Some aspects of the research themes of the participating groups are studied in collaboration, using a multi-disciplinary approach made possible by combining the know-how of the different groups. The central theme is regulation-mechanisms in the gastrointestinal tract. Specific goals are: a) NANC-neurotransmission, especially NO- and VIP-mediated; b) mechanism of action of motilin and motilides; and c) the interaction between the enteric nervous system and inflammatory mediators.

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              SKiN-HUID Specifieke Kankertherapie op basis van anx-Nanotechnologie op HUIDtumoren

              Kanker is één van de meest bedreigende ziekten van deze eeuw met jaarlijks wereldwijd 8 miljoen doden. De complexiteit van kanker maakt dat deze ziekte enkel succesvol behandeld kan worden door innovatie en vertaling van kennis naar nieuwe geneesmiddelen en behandelingsstrategieën.

              Onder leiding van Universiteit Maastricht streven Universiteit Antwerpen, VIB, Basic Pharma Technologies, and MosaMedix ernaar een antwoord te bieden op de specifieke uitdagingen van huidkanker. Dit consortium wordt financiëel ondersteund door het Interreg V programma van Interreg Vlaanderen-Nederland en EFRO (Europees Fonds voor Regionale Ontwikkeling).

               

              SKiN-HUID is een grensoverschrijdend project dat een unieke behandeling van huidkanker ontwikkelt op basis van een Anx-A5 gebaseerd platform voor ‘Target Drug Delivery’. Het omvat een gerichte toediening van medicijnen via elektrische of hyperthermische stimulatie die stress op de cellen zet. Voordelen van deze techniek zijn het efficiënt en doelgericht inkoppelen van toxische farmaceutische hoeveelheden, maar op basis van een verminderde dosis zodat algemene bijwerkingen beperkt blijven en de levenskwaliteit van de patiënt gehandhaafd blijft.

               

              De bedoeling is om deze technologie binnen ‘SKiN-HUID’ verder uit te spinnen tot een therapie, via preklinische en klinische validatie. Het VIB-labo van Prof. Chris Marine (KULeuven) voorziet hierin van wereldexpertise betreffende huidkanker en meer bepaald melanomas. Het labo waarvan Prof. John-Paul Bogers (UAntwerpen) deel uitmaakt, heeft een sleutelrol in biomedische microscopie en toxicologische analyse van proefdoermodellen. Tevens nemen zij een leidende rol op in het hyperthermie onderzoek. Met het labo van Prof. Chris Reutelingsperger (UMaastricht) heeft het project toegang tot unieke expertise en biochemische technologie over annexine. De Basic Pharma groep levert expertise en de faciliteiten voor de ontwikkeling van GMP productie en farmaceutische formuleringen, in samenwerking met MosaMedix, wat bijdraagt met zijn Annexine-technologie platform.