Research team

Laboratory of cell biology and histology

Expertise

- Cell biology of accelerated ageing diseases and neurodegeneration - Deep coverage microscopy for cellular profiling and drug screening

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.

Researcher(s)

Research team(s)

Deep phenotyping of cellular heterogeneity and maturation in human iPSC-derived brain organoids and cardiomyocytes. 01/01/2021 - 31/12/2024

Abstract

Pluripotent stem cell (PSC) technology is increasingly gaining interest for modelling diseases and developing precision therapeutics. However, the immaturity and heterogeneity of PSC-derived cell populations impinge on the reproducibility and preclude their use for comparative and diagnostic analyses. Recognizing these caveats for their own human induced (hi)PSC-based research, the Laboratories of Experimental Hematology, Cardiogenetics and Cell Biology and Histology have teamed up to develop a pipeline that enables accurate phenotypic staging of hiPSC-derived cell culture models. Specifically, to create mature and standardized 2D and 3D-models for cardiomyocyte cultures and brain organoids, our consortium proposes to optimize the culture conditions and refine the interrogation methods. Longitudinal follow-up and validation of functional activity in the differentiation products will be achieved by means of high-throughput multi-electrode array recordings and live cell calcium and voltage imaging. In parallel, cellular heterogeneity will be mapped with quantitative immunofluorescence and transcriptome analyses. The correlation of functional and molecular readouts will allow establishing a biomarker panel for mature hiPSC-derived cardiomyocyte models and brain organoids. Thus, with this work, we intend to develop more reproducible models and to allow selecting only those with the highest functional maturity, a prerequisite for our future stem cell research aimed at studying and treating neuro-inflammatory and cardiogenetic disorders.

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Synaptic Dysfuntion mediated by Alzheimer's disease-relevant Microglia (SynDAM). 01/07/2020 - 30/06/2022

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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Research team(s)

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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Multidimensional analysis of the nervous system in health and disease (µNeuro). 01/01/2020 - 31/12/2025

Abstract

Neuropathological research is an interdisciplinary field, in which imaging and image-guided interventions have become indispensable. However, the rapid proliferation of ever-more inquisitive technologies and the different scales at which they operate have created a bottleneck at the level of integration, a) of the diverse image data sets, and b) of multimodal image information with omics-based and clinical repositories. To meet a growing demand for holistic interpretation of multi-scale (molecule, cell, organ(oid), organism) and multi-layered (imaging, omics, chemo-physical) information on (dys)function of the central and peripheral nervous system, we have conceived μNEURO, a consortium comprising eight established teams with complementary expertise in neurology, biomedical and microscopic imaging, electrophysiology, functional genomics and advanced data analysis. The goal of μNEURO is to expedite neuropathological research and identify pathogenic mechanisms in neurodevelopmental and -degenerative disorders (e.g., Alzheimer's Disease, epilepsy, Charcot-Marie-Tooth disease) on a cell-to-organism wide scale. Processing large spatiotemporally resolved image data sets and cross-correlating multimodal images with targeted perturbations takes center stage. Furthermore, inclusion of (pre)clinical teams will accelerate translation to a clinical setting and allow scrutinizing clinical cases with animal and cellular models. As knowledge-hub for neuro-oriented image-omics, μNEURO will foster advances for the University and community including i) novel insights in molecular pathways of nervous system disorders; ii) novel tools and models that facilitate comprehensive experimentation and integrative analysis; iii) improved translational pipeline for discovery and validation of novel biomarkers and therapeutic compounds; iv) improved visibility, collaboration and international weight fueling competitive advantage for large multi-partner research projects.

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Research team(s)

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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Research team(s)

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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Research team(s)

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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Research team(s)

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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Research team(s)

Flanders BioImaging: towards an integrated, translational and multimodal imaging platform from molecule to man. 01/01/2019 - 31/12/2022

Abstract

Flanders BioImaging (FBI) is an interuniversity consortium dedicated to biomedical imaging and advanced light microscopy, that was set up to integrate, optimize, rationalize and coordinate available imaging infrastructure in Flanders.

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Research team(s)

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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Research team(s)

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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Research team(s)

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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Development of next-generation 3D brain organoids for the study and modulation of immunemediated neurodegeneration in cerebrovascular disease. 01/01/2018 - 31/12/2022

Abstract

Developing novel neuroprotective and/or immune-modulating therapeutic strategies for almost every neurological disease or trauma requires, both for academia and pharmaceutical industry, the existence of robust in vitro cell culture models to mimic disease-associated pathological events. Unfortunately, a complex interplay between multiple central nervous system (CNS) cell types and multiple cell types from the body's peripheral immune system, cannot be easily recapitulated by currently used 2-dimensional (2D) co-culture assays. It is exactly therefore that successful pre-clinical experimental efficacy has proved to be very difficult to translate into clinical benefit, and as a consequence there is an increasing gap in knowledge and progress between bench and bed side. One highly promising novel approach to improve the predictive power of in vitro human neuro-immune research consists in developing modular 3D brain organoids that resemble brain tissue at the structural, cellular and functional level. Within this project we aim to develop and optimize a new method for generating isogenic 3D brain organoids, comprising human pluripotent stem cell (hPSC)-derived neurons, astrocytes and microglia. Furthermore, hPSC-derived astrocytes and endothelial cells will be used to create a blood-brain-barrier model for physical separation of hPSC-derived macrophages from the generated human 3D brain organoids. Together, this integrated cell system will represent a powerful new 3D human neuro-immune cell culture paradigm. Within this multidisciplinary IOF-SBO project, the methodological approach to generate 3D brain organoids, combined with the experience in the field of clinical research and the availability of patient samples, is truly unique and will - in first instance - highly contribute to the field of in vitro cerebrovascular disease modelling and treatment validation. Furthermore, our aims to install an integrated 3D brain organoid technology platform at the University of Antwerp, will - given the current scientific and economic interests – allow for both short-term and long-term valorisation of our combined efforts, with both intellectual (PhD-theses, A1 publications) as well as financial (contract research) revenues.

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Research team(s)

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 team(s)

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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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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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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Research team(s)

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.

Researcher(s)

Research team(s)

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.

Researcher(s)

Research team(s)

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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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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Research team(s)

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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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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Research team(s)

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 team(s)

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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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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Research team(s)

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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Research team(s)

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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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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