Research Samir Kumar-Singh

Abstract

Colorectal cancer (CRC) is the third commonly diagnosed cancer and fourth cause of cancer death worldwide. An altered microbiome, also known as dysbiosis, can often be seen in CRC patients. Radiotherapy and immunotherapy are known treatment options for colorectal cancer, but are associated with toxicity and heterogeneous responses, respectively. Fecal microbiotal transplantation (FMT) has been shown to reduce radiation-induced toxicity and dysbiosis in mice and improve immunotherapy responsiveness in patients. To date, FMT has never been introduced with the dual therapy of radiotherapy and immunotherapy. Therefore, it is not clear whether this combined treatment will result in improved treatment outcome, lesser side-effects, tumor burden etc. In this project, we first intend to characterize the effects of dual radiotherapy and immunotherapy using the well-established azoxymethane (AOM)/dextran sodium sulfate (DSS) CRC mouse model. CRC mice will be treated with radiotherapy, immunotherapy or dual radiotherapy and immunotherapy, after which diagnostic microbial biomarkers for immunotherapy responsiveness and predictive microbial biomarkers of treatment outcome will be determined. Additionally, we plan to study if and how FMT can tackle radiation-induced dysbiosis and immunotherapy efficiency. Throughout the experiment, fecal samples will be collected and used to perform 16S microbial profiling. Tumor load (number, size, area), histo-pathological analysis (e.g. stem cell proliferation, apoptosis, mucus formation), inflammatory/immunological markers and proteomics analysis will be performed and correlated with the microbial dynamics to identify predictive and diagnostic biomarkers for treatment outcome and side-effects. Additionally, flow cytometry analysis, stainings and protein quantification assays for tight junctions will be used to assess bacterial translocation. FMT will be introduced in an anaerobic bag and similar experiments as explained above will be performed to determine if FMT can improve treatment outcome and side-effects. Meta-proteomics and meta-transcriptomics will be performed and will be integrated in an integrative omics analysis with the metagenomics to help understand the functional involvement of FMT in improving treatment outcome and side-effects.

Researcher(s)

• Promoter: Malhotra Surbhi
• Co-promoter: Kumar-Singh Samir

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: Timmermans Jean-Pierre
• Co-promoter: De Vos Winnok
• Co-promoter: Kumar-Singh Samir
• Co-promoter: Pintelon Isabel

Research team(s)

• Laboratory of cell biology and histology

Project website

Project type(s)

• Research Project

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)

• Promoter: De Vos Winnok
• Co-promoter: Baets Jonathan
• Co-promoter: Baggerman Geert
• Co-promoter: Bogers John-Paul
• Co-promoter: Keliris Georgios A.
• Co-promoter: Kumar-Singh Samir
• Co-promoter: Mertens Inge
• Co-promoter: Morrens Manuel
• Co-promoter: Staelens Steven
• Co-promoter: Stroobants Sigrid
• Co-promoter: Timmerman Vincent
• Co-promoter: Timmermans Jean-Pierre
• Co-promoter: Verhaeghe Jeroen
• Co-promoter: Verhoye Marleen
• Fellow: Lanens Dirk
• Fellow: Prasad Aparna

Research team(s)

• Laboratory of cell biology and histology

Project type(s)

• Research Project

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. ORCHESTRA aims to perform in-depth laboratory based assays on samples collected from Covid-19 patients during acute phase and during long-term sequelae as well as follow-up individuals post-vaccination. University of Antwerp laboratories are studying viral variants and the respiratory microbiome dynamics (Surbhi Malhotra) as well as analyzing the humoral and cell-mediated immune responses and cytokinome profiles (Samir Kumar -Singh). The laboratory analysis workpackage also aims to understand the role of human genetics, epigenetics and of the gut microbiome in disease pathogenesis and prognosis. This large consolidated wet-lab WP is led by the University of Antwerp. The project is funded by the European Union's Horizon 2020 research and innovation programme under the ERAvsCORONA Action Plan developed jointly by Commission services and national authorities.

Researcher(s)

• Promoter: Malhotra Surbhi
• Co-promoter: Kumar-Singh Samir

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: Kumar-Singh Samir
• Co-promoter: Malhotra Surbhi

Research team(s)

• Laboratory of cell biology and histology

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: Sijbers Jan
• Co-promoter: Baets Jonathan
• Co-promoter: Cras Patrick
• Co-promoter: De Vos Winnok
• Co-promoter: Giugliano Michele
• Co-promoter: Kumar-Singh Samir
• Co-promoter: Staelens Steven
• Co-promoter: Stroobants Sigrid
• Co-promoter: Timmerman Vincent
• Co-promoter: Timmermans Jean-Pierre
• Co-promoter: Verhoye Marleen
• Co-promoter: Weckhuysen Sarah

Research team(s)

• Vision lab

Project type(s)

• Research Project

Abstract

Antimicrobial resistance (AMR) is of great public health concern, causing numerous losses of lives worldwide and threatening to reverse many of the considerable strides modern medicine has made over the last century. There is a need to stratify antibiotic and alternative treatments in terms of the actual benefit for the patient, improving patient outcome and limit the impact on AMR. High quality, effective and appropriate diagnostic tests to steer appropriate use of antibiotics are available. However, implementation of these tests into daily healthcare practice is hampered due to lack of insight in the medical, technological and health economical value and limited knowledge about psychosocial, ethical, regulatory and organisational barriers to their implementation into clinical practice. VALUE-Dx will define and understand these value indicators and barriers to adoption of diagnostics of Community-Acquired Acute Respiratory Tract Infections (CA-ARTI) in order to develop and improve health economic models to generate insight in the whole value of diagnostics and develop policy and regulatory recommendations. In addition, efficient clinical algorithms and user requirement specifications of tests will be developed fuelling the medical and technological value of CA-ARTI diagnostics. The value of diagnostics will be tested and demonstrated in a unique pan-European clinical and laboratory research infrastructure allowing for innovative adaptive trial designs to evaluate novel CA-ARTI diagnostics. Close and continuous interaction with the VALUE-Dx multi-stakeholder platform provides for optimal alignment of VALUE-Dx activities with stakeholder opinions, expert knowledge and interests. A variety of dissemination and advocacy measures will promote wide-spread adoption of clinical and cost-effective innovative diagnostics to achieve more personalized, evidence-based antibiotic prescription in order to transform clinical practice, improve patient outcomes and combat AMR.

Researcher(s)

• Promoter: Goossens Herman
• Co-promoter: Coenen Samuel
• Co-promoter: Kumar-Singh Samir
• Co-promoter: Malhotra Surbhi

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

Infection with SARS-CoV-2 mostly leads to a mild self-limiting respiratory tract illness, however, some patients progress to develop severe progressive pneumonia, multiorgan failure, and death. The project aims to determine factors that dictate the severity of COVID-19. Firstly, guided by our prior data of interaction of certain mucins with the ACE2 receptor and the clinical evidence of excessive mucin production in severe COVID-19 illness, we intend to characterize different mucins for their role in both the initiation and progression of COVID-19. Secondly, based on a severe degree of edematous interstitial lung tissue pathology observed in COVID-19 autopsies and its hypothesized link to abnormally low PaO2 observed clinically, the project intends to characterize aquaporin (AQP) water channels that are responsible for fluid transport across cells. This has important therapeutic relevance for COVID-19 as specific AQP inhibitors have been shown to attenuate inflammation and lung injury and to block mucin hypersecretion. Lastly, mucin expression is also a critical factor in microbiome homeostasis and based on, so far, scarce data that co-infection with other respiratory pathogens and other microbial interactions might modulate COVID-19 severity, the project aims to characterize the microbiome associated with different degrees of disease severity. Identifying factors that shape the course of SARS-CoV-2 infection will lead to identification of plausible targets to treat COVID-19.

Researcher(s)

• Promoter: De Winter Benedicte
• Co-promoter: Jorens Philippe
• Co-promoter: Kumar-Singh Samir
• Co-promoter: Malhotra Surbhi
• Co-promoter: Smet Annemieke
• Co-promoter: Verstraeten Aline

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: Kumar-Singh Samir
• Co-promoter: Stroobants Sigrid
• Co-promoter: Timmermans Jean-Pierre
• Co-promoter: Vervaet Benjamin

Research team(s)

• Laboratory of cell biology and histology

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: Kumar-Singh Samir
• Co-promoter: Goossens Herman
• Fellow: Jairam Ravi Kumar

Research team(s)

• Laboratory of cell biology and histology

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: Kumar-Singh Samir
• Co-promoter: Malhotra Surbhi

Research team(s)

• Laboratory of cell biology and histology

Project type(s)

• Research Project

Abstract

This project aims to advance the currently available sequencing technologies at the University of Antwerp (UA) by acquiring a third generation sequencing (3GS) platform. The flagship of the third generation, single-molecule longread sequencers, PacBio Sequel, harnesses the natural process of DNA replication and enables real-time observation of DNA synthesis. 3GS promises to open new avenues for sequencing-based research beyond the current state-of-the-art for this consortium, which consists of more than 14 UA research groups in various disciplines of medicine, biology and bioinformatics. Furthermore, several third parties have also committed to utilize this technology for their ongoing and future research studies. 3GS will be utilized by this consortium to (i) sequence prokaryotic and eukaryotic genomes, and difficult-to-sequence genome regions, (ii) identify new genes and mutations in various rare Mendelian disorders, (iii) identify epigenetic modifications to better understand biological processes like gene expression and host-pathogen interactions, (iv) precisely profile the human, murine, and environmental microbiome in disease and under various environmental stressors, and (v) develop novel preventive therapies for infection-prone disorders for better drug targeting. The analysis of the large amount of genomic and transcriptomic data generated by the various research groups will be coordinated by the UZA/UA bioinformatics group Biomina.

Researcher(s)

• Promoter: Malhotra Surbhi
• Co-promoter: Kumar-Singh Samir
• Co-promoter: Laukens Kris
• Co-promoter: Mortier Geert
• Co-promoter: Smet Annemieke
• Co-promoter: Vanden Berghe Wim
• Co-promoter: Van Rie Annelies

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: Kumar-Singh Samir
• Fellow: Van Averbeke Vincent

Research team(s)

• Laboratory of cell biology and histology

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: Kumar-Singh Samir
• Fellow: 's Jongers Bart

Research team(s)

• Laboratory of cell biology and histology

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: De Vos Winnok
• Co-promoter: Bogers John-Paul
• Co-promoter: Kumar-Singh Samir
• Co-promoter: Maudsley Stuart
• Co-promoter: Timmerman Vincent
• Co-promoter: Van Der Linden Annemie

Research team(s)

• Laboratory of cell biology and histology

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: Kumar-Singh Samir

Research team(s)

• Laboratory of cell biology and histology

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: Goossens Herman
• Co-promoter: Kumar-Singh Samir
• Co-promoter: Malhotra Surbhi

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: Adriaensen Dirk
• Co-promoter: De Meester Ingrid
• Co-promoter: Kumar-Singh Samir
• Co-promoter: Lambeir Anne-Marie
• Co-promoter: Van Schil Paul

Research team(s)

• Laboratory of cell biology and histology

Project type(s)

• Research Project

Abstract

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

Researcher(s)

• Promoter: Maes Louis
• Co-promoter: Delputte Peter
• Co-promoter: De Meyer Guido
• Co-promoter: Dewilde Sylvia
• Co-promoter: Kumar-Singh Samir
• Co-promoter: Lambeir Anne-Marie
• Co-promoter: Lebeer Sarah
• Co-promoter: Leroy Jo
• Co-promoter: Van Cruchten Steven
• Co-promoter: Wenseleers Wim

Research team(s)

• Laboratory for Microbiology, Parasitology and Hygiene (LMPH)

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: Kumar-Singh Samir

Research team(s)

• Laboratory of cell biology and histology

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: Kumar-Singh Samir
• Fellow: Bielen Kenny

Research team(s)

• Laboratory of cell biology and histology

Project type(s)

• Research Project

Abstract

Our study proposes to firstly identify early predictors of pneumonia and secondly, utilize both human samples and rodent models to investigate distinct host-pathogen signatures during colonization and development of VAP by two marker organisms, Pseudomonas aeruginosa and Escherichia coli that not only show diverse pathogenetic profiles but are also most important for VAP etiology.

Researcher(s)

• Promoter: Goossens Herman
• Co-promoter: Kumar-Singh Samir
• Co-promoter: Malhotra Surbhi

Research team(s)

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: Kumar-Singh Samir

Research team(s)

• Laboratory of cell biology and histology

Project type(s)

• Research Project

Abstract

Chronic neurological diseases such as epilepsy and schizophrenia are difficult to manage and severely disabling disorders. Moreover, they are putting a huge burden on our social health care system. Currently, there is no available therapy that effectively halts or retards the development or progression of these conditions. The more we learn, the more it becomes clear that these neurological diseases are extremely complex as they do not have a well-understood mechanism of action and perhaps diverging dysfunctions, with evolving temporal and spatial aspects, may contribute to the disease. Remarkably, the manifestation of both diseases is preceded by a seemingly "silent" or "latent" period of several years without any apparent symptoms. Interestingly, scientific research suggests that this could be related to a neuronal insult during a critical phase of life, which initiates a series of pathophysiological processes during the latent period. At current, little research has been directed to investigate the latent period. As in patients, the chronic stage of the disease is represented rather than the early stage, the human research endeavour has been limited due to the difficulty to set-up these type of long-term prospective studies. As a consequence, our understanding of the processes occurring during this critical phase of the development of the disorder is incomplete. For instance, it is unknown what factors contribute to the phenomenon that only a subgroup of individuals will eventually be affected by the disorder. A better insight in these events could potentially lead to early identification of patients at risk. It has been speculated that neuroinflammation plays an important role in the reorganisation of the neuronal network after the occurrence of a traumatic event. The current project will follow the development of neuroinflammation together with the investigation of the functional integrity of the brain in laboratory animals utilising imaging biomarkers. The recent advances in dedicated in vivo imaging techniques for small animal brain imaging, such as positron emission tomography (PET), allow scientist for the first time to conduct basic research in a non-invasive and longitudinal manner, facilitating translation of knowledge from bench side to clinical application. This study will add very important new information about the contribution of neuroinflammation to the development of neurological disorders such as epilepsy and schizophrenia, its consequences for the functional integrity of the brain and whether these biomarkers could contribute to the early identification of patients as risk. Non-invasive imaging using biomarkers is an upcoming and promising new approach, which clearly allows for translation of applications to the clinic. The outcomes of this research will inform clinical practice, particularly providing rationale for the implementation of potentially neuroprotective strategies to slow down or halt this degeneration, as well as potentially providing a method to assess the biological efficacy of prospective new therapies prior to the institution of expensive human trials.

Researcher(s)

• Promoter: Dedeurwaerdere Stefanie
• Co-promoter: Kumar-Singh Samir
• Co-promoter: Staelens Steven

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Progranulin (GRN) is a multifunctional secreted growth factor expressed in a wide variety of tissues including the central nervous system (CNS). GRN is involved in various important cellular functions including cell cycle progression, cell motility, wound repair and inflammation and loss of GRN is associated with frontotemporal dementia (FTD). The precise mechanisms underlying GRN-mediated cell proliferation and neuronal survival as well as a link with TDP-43, that is cleaved, phosphorylated and deposited as intraneuronal inclusions in FTD patients, are not yet well understood. In the first part of this project we showed that loss of Grn in mixed cortical cultures led to increased caspase activation and decreased TDP-43 solubility. In the next term we will investigate the precise cell types responsible for the observed GRN-dependent phenotype. We will therefore study whether this neurodegenerative phenotype is caused by an intrinsic defect of the neurons, a defect of glial cells (e.g. astrocytes), which can not support the survival of neurons, or a combination of both. Therefore we aim to establish conditional astrocyte-specific Grn knockout mice as well as primary glial cultures from Grn-/- and wild-type mice which will then be analyzed for signs of increased cellular stress or degeneration like caspase-3/7 activity, TUNEL staining, expression of cell stress molecules etc.. The biochemical properties of TDP-43 in astrocytes such as sub-cellular localization, processing and any pathological alterations due to Grn loss, like increased TDP-43 phosphorylation, insolubility, fragmentation and "nuclear clearing", will be investigated by both immoncytochemistry and immunoblotting techniques. Co-cultures of primary wild-type neurons on astrocyte feeder layers of Grn-/- or wild-type mice will be used to study alterations in neuronal differentiation, polarization and increased signs of degeneration like decreased levels of synaptic proteins on immunocytochemistry, decreased neuritic growth/axonal length by fiber tracking experiments, and morphological appearance of de-differentiation. Furthermore co-cultures experiments will be used to investigate any reduced capacity of Grn-/- astrocytes to protect neurons from neurotoxicity. Continued characterization of the described cellular models would provide us important insights in the underlined mechanisms by which Grn haploinsufficiency causes decreased neuronal survival.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: Kumar-Singh Samir
• Fellow: Kleinberger Gernot

Research team(s)

Project type(s)

• Research Project

Abstract

Amyloid-ß (Aß) aggregation in brain parenchyma as amyloid plaques is a neuropathological hallmark of Alzheimer's disease (AD). Interestingly, only dense-core plaques are associated with neuritic and inflammatory pathology in AD patients as well as in mouse AD models. However, the precise neuropathological changes that occur in brain in response to amyloid deposition are largely unknown. Several lines of evidence suggest that Aß does not aggregate spontaneously in brain but is rather assisted by specific chaperones that help Aß to aggregate into ß-sheets. Utilizing transcriptomic and proteomic analysis, the project aims to elucidate the mechanism(s) of dense-core plaque formation in various plaque-depositing transgenic mouse AD models. Interestingly, we have shown in an unbiased transcriptomic analysis that progranulin is upregulated in microglia, neurons and neurites in association with dense-core plaques in brains of Tg2576 and APPPS1 mice, as has also been shown for AD patients, which prompts for testing progranulin as a biomarker for human studies. To further investigate the role of progranulin in AD pathogenesis, we have crossed APPPS1 mice with progranulin overexpression and progranulin knock-out mice. These studies would aid in developing novel potential therapeutic strategies for preventing or treating Alzheimer's disease.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: Kumar-Singh Samir
• Fellow: Pereson Sandra

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: Kumar-Singh Samir
• Fellow: Van Cauwenberghe Caroline

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Cruts Marc
• Co-promoter: Kumar-Singh Samir

Research team(s)

Project type(s)

• Research Project

Abstract

Dementias are the fourth leading cause of death, affecting more than 30 million individuals worldwide. Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) are the two most common causes of cortical dementia in the presenium. FTLD comes in various forms and the most common type is the one where ubiquitinated proteins are deposited in neurons and glial cells both within the cytoplasm and the nucleus (where they are typically cat eye-shaped). This form is called FTLD-U (U for ubiquitin). Very recently, mutations that do not allow the functional protein to be produced have been identified in the progranulin (GRN) gene as a cause of FTLD-U and interestingly, a protein called TDP-43 has also been identified as one of the major constituents of the neuronal and glial cell inclusions. Both progranulin and TDP-43 are important proteins with many functions, but their precise function in brain and neurodegeneration remains unknown as does the link between progranulin and TDP-43. The project aims to build knockout and transgenic mouse models to study how loss of GRN protein could cause neurodegeneration and how it could be linked to TDP43 aggregation. The clues gained from these models will also be important to prevent and/or treat other forms of neurodegeneration such as AD and amyotrophic lateral sclerosis.

Researcher(s)

• Promoter: Kumar-Singh Samir

Research team(s)

Project type(s)

• Research Project

Abstract

Progranulin (GRN) is a growth factor involved in tumorogenesis, while loss of GRN leads to frontotemporal dementia (FTD). The precise mechanisms underlying GRN-mediated cell proliferation and neuronal survival as well as a link with TDP43, that is cleaved, phosphorylated and deposited as intraneuronal inclusions in FTD patients, are not well understood. The project aims at developing GRN and TDP43 overexpression and deficient cellular models including primary neuronal cells derived from Grn-/- mice to study the biochemistry and interaction of GRN and TDP43 in disease context. These models will be established using siRNA mediated protein knockdown and expression of tagged/untagged GRN and TDP43 proteins. We will study GRN-mediated cell proliferation as well as other phenotypes using cellular assays such as BrdU proliferation, flow cytometry and caspase-luminescence assays. The established models will also be utilized to study subcellular localization, protein trafficking and turnover of endogenous and/or overexpressed GRN and TDP43 as well as altered signaling pathways. Furthermore the link between GRN deficiency and TDP43 phosphorylation, fragmentation and accumulation will be elucidated in these cell models. Characterization of these cellular models would give us important insights in the mechanisms by which GRN haploinsufficiency causes decreased neuronal survival.

Researcher(s)

• Promoter: Kumar-Singh Samir
• Promoter: Van Broeckhoven Christine
• Co-promoter: Kumar-Singh Samir
• Co-promoter: Van Broeckhoven Christine
• Fellow: Kleinberger Gernot

Research team(s)

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: Kumar-Singh Samir

Research team(s)

• Laboratory of cell biology and histology

Project type(s)

• Research Project

Abstract

The project aims to employ molecular genetic and pathological studies to further understand the role of progranulin (PGRN) in dementia, and to elucidate the role of modifier genes in the clinicopathological expression of PGRN mutations. These studies will allow designing an optimized protocol for molecular genetic diagnostics. Further, genes modifying disease onset and progression are likely to be effective targets for therapeutic interventions e.g. aiming at disease delay. Furthermore, this project also aims to build mouse and cellular PGRN knockout models - PGRN -/+ and PGRN -/- knockout mice, derived PGRN -/- primary rodent neurons, and siRNA treated immortalized cells - that would serve to elucidate whether and how PGRN loss leads to decreased cell survival and more specifically of the cortical neurons. The cellular models would allow elucidating PGRN cellular trafficking and catabolism as well as the underlying cell signaling pathways that are down regulated in PGRN deficiency. The specific aims of the project are: to evaluate the occurrence of complex PGRN null-mutations in a collection of 190 Belgian FTLD patients as well as study the contribution of PGRN mutations in FTLD-associated neurodegenerative diseases including PD, ALS and AD, to identify genes modifying the highly variable onset age of FTDU associated with PGRN mutations, to construct PGRN knockout mice and illustrate whether PGRN -/+ and PGRN -/- mice have neuronal loss especially in the basal forebrain or develop behavioral or cognitive abnormalities compared to the wild-type mice or to mice overexpressing human wild-type PGRN, and to develop PGRN overexpressing and deficient cellular models and to utilize these models to study overexpressed and/or endogenous PGRN cellular localizations and protein trafficking and turnover.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: Cruts Marc
• Co-promoter: Kumar-Singh Samir

Research team(s)

Project type(s)

• Research Project

Abstract

Amyloid-ß (Aß) aggregation in brain parenchyma as dense-core and diffuse plaques, and in vascular walls, are a major neuropathological feature of Alzheimer's disease. Dense-core plaques are considered neurotoxic. Several lines of evidence suggest that Aß does not aggregate spontaneously in brain but is rather assisted by specific chaperones that help Aß to aggregate into ß-sheets. We recently identified vessels to be a major site where dense-core plaques develop in both transgenic mouse models and patients of Alzheimer's disease, suggesting that vessels are a hot-spot for such Aß assembly-promoting factors. Interestingly, vessels free of Aß deposition have also been shown to have a number of structural microvascular abnormalities in both Alzheimer's patients and transgenic mouse models suggesting that vascular pathology is also important in the pathogenesis of Alzheimer's disease. Utilizing transcriptomic and proteomic analysis, the current project aims to elucidate the mechanism(s) of dense-core plaque formation at vascular sites as well as to understand changes that occur in these vessels prior to plaque deposition in various transgenic mouse models of Alzheimer's disease. These studies would in turn further aid in identifying novel potential therapeutic targets for preventing or treating Alzheimer's disease.

Researcher(s)

• Promoter: Kumar-Singh Samir
• Co-promoter: Van Broeckhoven Christine
• Fellow: Pereson Sandra

Research team(s)

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: Kumar-Singh Samir
• Fellow: Kumar-Singh Samir

Research team(s)

• Laboratory of cell biology and histology

Project type(s)

• Research Project

Abstract

Recently, mutations in progranulin (GRN) were identified as the cause of the most common form of frontotemporal dementia (FTD-U). Most of these mutations are null mutations, suggesting that reduced levels of GRN protein are at the basis of the disease pathomechanism. Also recently, the TAR DNA binding protein (TDP43) was identified as a major constituent of the intraneuronal nuclear and cytoplasmic inclusions typically found in FTD-U. This project aims to develop progranulin knockout mice (Grn-/+ and Grn-/-) and human GRN and TDP43 overexpression mouse models that would serve to elucidate whether and how progranulin loss leads to decreased cell survival, specifically of the cortical neurons. Behavioral or cognitive abnormalities compared to the wild-type mice or to mice overexpressing human GRN will also be studied. However, because GRN/Grn is an important gene expressed in a variety of tissues, the targeting construct utilizes a conditional knockout approach that can be used if the constitutive Grn loss is embryonically lethal. Also, targeted Grn ablation in neurons or neuroglia will be studied with this construct. Lastly, we will generate crossbred Grn-/- x TDP43 overexpressing mice to study possibly accelerated TDP43 pathology. These mouse models would serve as both disease model and mechanism model on which novel therapeutic approaches could be tested in the future.

Researcher(s)

• Promoter: Kumar-Singh Samir
• Co-promoter: Van Broeckhoven Christine
• Fellow: Wils Hans

Research team(s)

Project type(s)

• Research Project

Abstract

Progranulin (GRN) is a growth factor involved in tumorogenesis, while loss of GRN leads to frontotemporal dementia (FTD). The precise mechanisms underlying GRN-mediated cell proliferation and neuronal survival as well as a link with TDP43, that is cleaved, phosphorylated and deposited as intraneuronal inclusions in FTD patients, are not well understood. The project aims at developing GRN and TDP43 overexpression and deficient cellular models including primary neuronal cells derived from Grn-/- mice to study the biochemistry and interaction of GRN and TDP43 in disease context. These models will be established using siRNA mediated protein knockdown and expression of tagged/untagged GRN and TDP43 proteins. We will study GRN-mediated cell proliferation as well as other phenotypes using cellular assays such as BrdU proliferation, flow cytometry and caspase-luminescence assays. The established models will also be utilized to study subcellular localization, protein trafficking and turnover of endogenous and/or overexpressed GRN and TDP43 as well as altered signaling pathways. Furthermore the link between GRN deficiency and TDP43 phosphorylation, fragmentation and accumulation will be elucidated in these cell models. Characterization of these cellular models would give us important insights in the mechanisms by which GRN haploinsufficiency causes decreased neuronal survival.

Researcher(s)

• Promoter: Kumar-Singh Samir
• Co-promoter: Van Broeckhoven Christine
• Fellow: Kleinberger Gernot

Research team(s)

Project type(s)

• Research Project

Abstract

Amyloid-ß (Aß) aggregation in brain parenchyma as dense-core and diffuse plaques, and in vascular walls, are a major neuropathological feature of Alzheimer's disease. Dense-core plaques are considered neurotoxic. Several lines of evidence suggest that Aß does not aggregate spontaneously in brain but is rather assisted by specific chaperones that help Aß to aggregate into ß-sheets. We recently identified vessels to be a major site where dense-core plaques develop in both transgenic mouse models and patients of Alzheimer's disease, suggesting that vessels are a hot-spot for such Aß assembly-promoting factors. Interestingly, vessels free of Aß deposition have also been shown to have a number of structural microvascular abnormalities in both Alzheimer's patients and transgenic mouse models suggesting that vascular pathology is also important in the pathogenesis of Alzheimer's disease. Utilizing transcriptomic and proteomic analysis, the current project aims to elucidate the mechanism(s) of dense-core plaque formation at vascular sites as well as to understand changes that occur in these vessels prior to plaque deposition in various transgenic mouse models of Alzheimer's disease. These studies would in turn further aid in identifying novel potential therapeutic targets for preventing or treating Alzheimer's disease.

Researcher(s)

• Promoter: Kumar-Singh Samir
• Co-promoter: Van Broeckhoven Christine
• Fellow: Pereson Sandra

Research team(s)

Project type(s)

• Research Project

Abstract

This network project is designed to apply the unique information provided by sequencing of the human genome to further the understanding of and to develop treatments for neurodegenerative diseases. The association in the proposed network of research groups in clinical research, human genetics and genomics, cell biology, proteomics, bioinformatics, and model organisms (mice, zebrafish and Drosophila), will create an integrated network that should allow identification of novel disease genes, determination of their biological functions, establishing their role in pathophysiological processes and identification of novel avenues for early diagnosis, treatment and prevention. The network will focus its research activities on diseases of the central nervous system (CNS) such as Alzheimer disease, Parkinson disease, frontotemporal dementia and related diseases; and diseases of peripheral nervous system (PNS) such as peripheral motoneuronopathies, amyotrophic lateral sclerosis and related disorders.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: Cruts Marc
• Co-promoter: Kumar-Singh Samir

Research team(s)

Project type(s)

• Research Project

Abstract

The general aim of this project is to contribute to a bettter knowledge of the genetic etiology of AD. This knowledge is expected to provide a better insight in the genetic risk profile of a human being (early detection) and in the biology of the disease process in brain (neuropathology/biology). Specific aims: 1. Collection of materials for genetic studies of AD patients and families. 2. Genetic characterization of AD patients and genotype-phenotype correlations. 3. Identification of novel chromosomal loci and genes for AD 4. Identification of novel risk and protection factors for AD 5. Neuropathological and neurobiological analysis of AD mutations/genes.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: Cruts Marc
• Co-promoter: Kumar-Singh Samir

Research team(s)

Project type(s)

• Research Project

Abstract

This PhD project intends to study the role of progranulin (PGRN) in frontotemporal demntia (FTD) with both in vitro experiments and in vivo mouse models. In vitro RNA interference (RNAi) techniques will be utilized to study if reduced PGRN expression causes decreased survival of cultivated neuronal cells and primary neurons. In vivo a PGRN constitutive and conditional knock-out mouse model will be developed. On these mice I will study the function of PGRN in brain and how PGRN loss causes neurodegeneration specifically of the neurons of the forebrain. Finally, primary neuronal cultures derived from different regions of rodent brain will also be examined ex vivo to study PGRN expression patterns and to elucidate why loss of PGRN is more critical to neurons of the forebrain.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: Kumar-Singh Samir
• Fellow: Wils Hans

Research team(s)

Project type(s)

• Research Project

Abstract

Amyloid-ß (Aß) aggregation in brain parenchyma as dense-core and diffuse plaques, and in vascular walls, are a major neuropathological feature of Alzheimer's disease. Dense-core plaques are considered neurotoxic. Several lines of evidence suggest that Aß does not aggregate spontaneously in brain but is rather assisted by specific chaperones that help Aß to aggregate into ß-sheets. We recently identified vessels to be a major site where dense-core plaques develop in both transgenic mouse models and patients of Alzheimer's disease, suggesting that vessels are a hot-spot for such Aß assembly-promoting factors. Interestingly, vessels free of Aß deposition have also been shown to have a number of structural microvascular abnormalities in both Alzheimer's patients and transgenic mouse models suggesting that vascular pathology is also important in the pathogenesis of Alzheimer's disease. Utilizing transcriptomic and proteomic analysis, the current project aims to elucidate the mechanism(s) of dense-core plaque formation at vascular sites as well as to understand changes that occur in these vessels prior to plaque deposition in various transgenic mouse models of Alzheimer's disease. These studies would in turn further aid in identifying novel potential therapeutic targets for preventing or treating Alzheimer's disease.

Researcher(s)

• Promoter: Kumar-Singh Samir

Research team(s)

Project type(s)

• Research Project

Abstract

Most cases of neurodegenerative brain diseases like Alzheimer's Disease (AD) or Parkinson's disease (PD) appear sporadically, whereas familial cases are rare. The genetic factors involved are, for example, APP- and presenilin genes in AD and a-synuclein and parkin genes in PD. Mutations in these genes will be studied in vitro, by cell culture experiments, as well as in vivo, in transgenic mouse models. It is expected that these studies will allow us to improve our understanding of the pathogenic mechanisms of the genetic as well as the sporadic forms of these diseases.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: Kumar-Singh Samir
• Fellow: Van Broeck Bianca

Research team(s)

Project type(s)

• Research Project

Abstract

The general aim of this project is to contribute to a better understanding of the genetic etiology of familial and sporadic FTD. Specific aims are: 1) Collection of FTD patients and families, 2) Identification of the genetic defect in FTDU-17, 3) Identification of novel FTD loci and 4) Genetic association study of MAPT in FTD patient populations.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: Cruts Marc
• Co-promoter: Kumar-Singh Samir

Research team(s)

Project type(s)

• Research Project

Abstract

Presenilins (PS 1 and 2) are integral components of the gamma-secretase complex which is responsible for the cleavage of a number of transmembranous proteins including amyloid precursor protein (APP) and Notch. Mutations within PS1 are primary cause of familial Alzheimer's disease (FAD). It is assumed that PS mutations cause FAD due to the "amyloid cascade" where Aß accumulation lies upstream of tau phosphorylation and neurodegeneration. However, increasing evidence suggests that PS might directly interact with tau and tau kinases. Our departement identified a PS1 mutation (G183V) causing frontotemporal dementia (FTD) of the Pick's disease type. In this disease, patients present with progressive changes in behavior or language dysfunction and it is an important cause of dementia in patients younger than 65 years of age.The aim of this project is to study the underlying mechanisms of tau accumulation due to PS1 G183V in cellular and mouse models. These models might shed light on how a pathological PS1 mutation could trigger tau pathology and/or neurodegeneration.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: Kumar-Singh Samir
• Fellow: Wils Hans

Research team(s)

Project type(s)

• Research Project

Abstract

In this project our main focus will be on the identification and characterization of the genetic defect underlying the pathology in frontotemporal dementia (FTD) characterized by tau-negative but ubiquitine-positive staining neuronal inclusions (FTD-U), more specifically FTD-U linked to chromosome 17q21 or FTDU-17. FTD dementias are the most frequent form of neurodegenerative dementias next to Alzheimer dementia (AD), FTD-U represents a major FTD subform, but its frequency is not well known though likely underestimated. Currently, we have no clear knowledge of the molecular cause of FTD-U neurodegeneration, though it would allow modelling the pathophysiology in cells and animal models. These models, as for other dementias like AD, form the basis for research towards understanding the biology of neurodegeneration per se and development of effective therapies. FTD represents approximately 5% of all dementia patients and 10-20% of patients with an onset age below 65 years. FTD patients present personality changes and disinhibited behaviour, often accompanied by gradual and progressive language dysfunctions. Neuropathological examination identified 3 broad groups: patients with tau-positive pathology or FTD¿, with tau-negative but ubiquitine-positive pathology or FTD-U and those lacking distinctive histopathology or DLDP. In general only a third of all FTD patients had FTD¿, conversely the relative contributions of FTD-U and DLDH significantly varied. A positive family history of dementia is found in approximately 40% of FTD patients and in the majority of these patients the disease is inherited as an autosomal dominant trait. Recent studies have shown that 10-43% of all familial FTD patients are associated with mutations in the gene encoding the tau protein (MAPT) located at 17q21. To date, 36 different MAPT mutations have been identified in 106 dementia families worldwide. However, in at least 4 autosomal dominant FTD families linked to 17q21 mutations in MAPT were not identified. The latter stimulated many researchers to analyse extended FTD families with unknown genetic cause, resulting in an increasing number of FTDU-17 families suggesting a higher frequency than previously predicted. Also, while more pathological data became available it seems that the majority ¿ if not all ¿ of these families belong to the FTD-U subtype. Together, the current data indicate that identification of the underlying gene defect in FTDU-17 might significantly contribute to our understanding of the pathomechanism leading to neurodegeneration in this dementia subtype. We will use molecular genetic and pathological studies to identify the genetic defect in FTDU-17. We previously defined the smallest candidate region of 4.8 cM in one Dutch-Netherlands FTDU-17 family 1083. Recently we identified 3 Dutch-Belgian FTDU-17 families and showed by haplotype analysis a founder effect in Flanders, the Dutch-speaking region of Belgium. In addition, we aim at characterizing the inclusion pathology and proteinopathy by immunohistochemistry and/or by mass spectrometric analysis of laser-dissected and enriched ubiquitin-positive aggregates from frozen FTDU-17 brains. We expect that the identification of the FTDU-17 defect will contribute to the differential diagnosis of FTD, to the generation of cellular and animal models for FTDU-17 and finally to a better understanding of the neurodegenerative process in general that should contribute to the development of a more effective therapy for dementia.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: Cruts Marc
• Co-promoter: Kumar-Singh Samir

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Kumar-Singh Samir

Research team(s)

Project type(s)

• Research Project

Abstract

Neurodegenerative dementias are the most common diseases of the aging population representing major medical, social and economic problems. The disease processes are not yet fully understood and no effective treatment is available. This project aims at identifying and characterizing novel neurodegenerative dementia genes more particularly of Alzheimer's and frontotemporal dementias. This will help to understand pathological processes and identify novel drug targets.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: Cruts Marc
• Co-promoter: Kumar-Singh Samir

Research team(s)

Project type(s)

• Research Project

Abstract

Most cases of neurodegenerative brain diseases like Alzheimer's Disease (AD) or Parkinson's disease (PD) appear sporadically, whereas familial cases are rare. The genetic factors involved are, for example, APP- and presenilin genes in AD and a-synuclein and parkin genes in PD. Mutations in these genes will be studied in vitro, by cell culture experiments, as well as in vivo, in transgenic mouse models. It is expected that these studies will allow us to improve our understanding of the pathogenic mechanisms of the genetic as well as the sporadic forms of these diseases.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: Kumar-Singh Samir
• Fellow: Van Broeck Bianca

Research team(s)

Project type(s)

• Research Project

Abstract

Degenerative disorders of the nervous system including Alzheimer's, Parkinson's, Huntington's, motor neuron and prion diseases are among the most debilitating illnesses, putting an enormous strain on both social and health care budgets in Europe. As these diseases progress, all but the most primitive functions of the nervous system are lost due to the degeneration and subsequent death of nerve cells. Eventually patients die in a state of incapacitation. Only a small fraction of cases can be accounted for by gene mutations. Altogether, the underlying aetiologies are poorly understood. A hallmark common to these neurodegenerative disorders is the deposition of abnormal protein aggregates. There is currently no treatment available that can halt or prevent, let alone reverse nerve cell degeneration. The APOPIS project is designed to apply the unique information provided by sequencing of the human genome to further the understanding of and to develop treatments for these devastating diseases. By integrating Europe¿s leading research centres in clinical research, human genetics, cell biology, genomics, proteomics and bioinformatics, the VERUM Foundation has devised a consortium to identify genes involved, determine their biological functions, establish their role in the pathophysiological processes and identify novel avenues for early diagnosis, treatment and prevention. The chosen approach is based on human population genetics complemented by the identification of modifier genes in model organisms that express both wildtype and mutant variants of known disease-related genes. The consortium meets the prerequisites for such a project: ground breaking research in functional genomics related to human health, creating synergies with and between national research efforts, teaming up with both small biotechnology and pharmaceutical companies for the development of diagnostic tools and new drugs, and providing training and mobility to improve the skills of young researchers.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: Cruts Marc
• Co-promoter: Kumar-Singh Samir

Research team(s)

Project type(s)

• Research Project

Abstract

Degenerative disorders of the nervous system including Alzheimer's, Parkinson's, Huntington's, motor neuron and prion diseases are among the most debilitating illnesses, putting an enormous strain on both social and health care budgets in Europe. As these diseases progress, all but the most primitive functions of the nervous system are lost due to the degeneration and subsequent death of nerve cells. Eventually patients die in a state of incapacitation. Only a small fraction of cases can be accounted for by gene mutations. Altogether, the underlying aetiologies are poorly understood. A hallmark common to these neurodegenerative disorders is the deposition of abnormal protein aggregates. There is currently no treatment available that can halt or prevent, let alone reverse nerve cell degeneration. The APOPIS project is designed to apply the unique information provided by sequencing of the human genome to further the understanding of and to develop treatments for these devastating diseases. By integrating Europe¿s leading research centres in clinical research, human genetics, cell biology, genomics, proteomics and bioinformatics, the VERUM Foundation has devised a consortium to identify genes involved, determine their biological functions, establish their role in the pathophysiological processes and identify novel avenues for early diagnosis, treatment and prevention. The chosen approach is based on human population genetics complemented by the identification of modifier genes in model organisms that express both wildtype and mutant variants of known disease-related genes. The consortium meets the prerequisites for such a project: ground breaking research in functional genomics related to human health, creating synergies with and between national research efforts, teaming up with both small biotechnology and pharmaceutical companies for the development of diagnostic tools and new drugs, and providing training and mobility to improve the skills of young researchers.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: Cruts Marc
• Co-promoter: Kumar-Singh Samir

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Kumar-Singh Samir
• Co-promoter: Theuns Jessie

Research team(s)

Project type(s)

• Research Project

Abstract

Most cases of neurodegenerative brain diseases like Alzheimer's Disease (AD) or Parkinson's disease (PD) appear sporadically, whereas familial cases are rare. The genetic factors involved are, for example, APP- and presenilin genes in AD and a-synuclein and parkin genes in PD. Mutations in these genes will be studied in vitro, by cell culture experiments, as well as in vivo, in transgenic mouse models. It is expected that these studies will allow us to improve our understanding of the pathogenic mechanisms of the genetic as well as the sporadic forms of these diseases.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: Kumar-Singh Samir
• Fellow: Van Broeck Bianca

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Co-promoter: Cruts Marc
• Co-promoter: Kumar-Singh Samir

Research team(s)

Project type(s)

• Research Project

Abstract

We recently identified a novel mutation in an Alzheimer's disease (AD) gene that leads to deposition of brain amyloid ß (Aß) as unusual diffuse plaques, rather than the classical compact plaques. One of the most severe AD features present in these patients fits well with recent in vitro data suggesting that early Aß conformational states could be the real culprit. We intend to test this hypothesis on a correlative neuropathological, biochemical, and neuro MRI studie on mice overexpressing this mutant gene.

Researcher(s)

• Promoter: Kumar-Singh Samir
• Co-promoter: Van Der Linden Annemie

Research team(s)

Project type(s)

• Research Project