Title Promoter Affiliations Abstract "An integrated approach of genetic epidemiology and molecular genetics in the study of Alzheimer dementia and related phenotypes." "Christine Van Broeckhoven" "VIB CMN - Neurodegenerative Brain Diseases Group" "This project aims to contribute to a better understanding of the genetic etiology of complex forms of Alzheimer dementia by means of genetic-epidemiological and molecular genetic techniques. This will help in identifying molecular mechanisms that can serve as targets for early detection, prevention and treatment of this common and incurable disease. High-throughput association studies (both genome-wide and focused on biological pathways) and intermediary or endophenotypes will be performed in a well-characterized study population with sufficient statistical power. Translation of findings to prodromal stages of AD will point out which factors are already of relevance early in the pathological cascade. These factors might find use as early predictors. Pathway analysis will identify subgroups with an increased epidemiological risk profile. In addition, we will assess if these prognostic markers affect easily measurable quantitative traits, e.g. in an integrated study of genome wide genotype data and differential protein expression in a proteomics study. If a correlation can be demonstrated, this trait can be used as a biomarker specific to the disease process. In addition we aim to identify genetic factors that modify onset age, to find novel targets for treatment, to delay or prevent the pathological cascade." "Characterizing genes and molecular mechanisms involved in frontotemporal lobar degeneration (FTLD) using an integrated approach of molecular genetics and functional genomics." "Marc Cruts" "VIB CMN - Neurodegenerative Brain Diseases Group" "In this project, we will apply an integrated approach of molecular genetic and functional genomic strategies to identify novelgenes causing FTLD, modifying one's risk to develop FTLD, and/or altering clinical expression of the disease. Further, we will identify functional pathways and cellular processes that are affected in FTLD. Studies of the function and dysfunction of FTLD genes and pathways will greatly expand our knowledge of neurodegenerative disease mechanisms." "A molecular epidemiological approach to senescence: influence of early life environmental exposure on (epi) genetics" "Tim NAWROT" "Environmental Biology" "Ageing is a process influenced both by genetic variation and environmental factors. Environmental factors are all factors that influence this process from outside of the organism, for example smoking, pollution and exercise. Epigenetics is the study of changes in gene activity that do not involve alterations to the genetic code but still get passed down to at least one successive generation. Epidemiology is the study of the patterns, causes and effects of health and disease conditions in defined populations. A big advantage of epidemiologic research is that it looks at people in their 'natural' environment, and looks to explain the differences between people within a population. Age is an important factor that influences how people adapt to environmental exposures. We know that ageing already starts in utero. In utero exposures impact the newborn, but we believe they also have an impact on development of adult-onset disease. The ENVIRONAGE birth cohort currently consists of 560 mother-newborn pairs and enrollment is still ongoing while structured follow-up measures of cardiovascular phenotypes have been initiated. I will study early signs / patterns of ageing in association with environmental factors at the molecular level. To this end, I study epigenetic changes induced by early life exposures in age related pathways and I want to unravel the meaning of these pathways in early life variation of cardiovascular phenotypes of both the micro- and macro-circulation." "Molecular genetics and biomarker research of frontotemporal lobar degeneration supported by robust biosampling and biobanking strategies." "Christine Van Broeckhoven" "VIB CMN - Neurodegenerative Brain Diseases Group" "In the past decade remarkable advances have been made in understanding the origin of frontotemporal lobar degeneration (FTLD), after Alzheimer's disease one of the leading causes of dementia. In sharp contrast however, is the absence of any therapeutic strategy based on these novel discoveries and the fact that a significant portion of patients remains in which the source of the disease is still unknown. This research project proposes an integrated approach to further uncover the genetic etiology of FTLD. This includes the establishment of a centralized repository of tissues and biofluids from medically and molecularly thoroughly characterized, extended collections of FTLD patients and unaffected individuals (biobank). This powerful biobank will allow the set-up of state of the art genetic studies of FTLD. We will participate to international large scale genome-wide association studies aiming to discover genetic risk factors for FTLD. We will further investigate these findings in our population of Flanders- Belgian FTLD patients to examine population-specific risk profiles. Moreover, the biobank will facilitate translation of knowledge obtained from these basic molecular research studies into clinical applications for improved diagnosis and treatment of future patients." "Molecular genetics of mantle cell lymphoma." "Iwona Krajewska" "Laboratory for Genetics of Malignant Disorders, Translational Cell & Tissue Research, Department of Human Genetics" "Mantle cell lymphoma (MCL) is a well-defined B-cell neoplasm with a poor prognosis and a short survival. MCL is hallmarked by t(11;14)(q13;q32) that leads to overexpression of cyclin D1, an important regulator of the G1 phase of the cell cycle. This tumor shows the high level of genomic instability, reflected by complex karyotypes and numerous non-recurrent secondary aberrations likely playing an important role in disease maintenance and progression. Genomic abnormalities in MCL have not been fully explored and targets of many secondary changes that could contribute to development and progression of MCL in concert with t(11;14) await identification. The proposed project aims at comprehensive analysis of a large series of MCL using the most recent cytogenetic modalities and high resolution genomic scanning platforms. We collected 300 cytogenetically documented MCL cases including 80 cases with 1-6 consecutive biopsies. Genome of these lymphomas will be profiled using the next generation genomic arrays able to detect submicroscopic genomic aberrations with the highest available resolution of 300-1000 bp. Studying in a genomic-wide fashion diagnostic and follow up MCL biopsies, we will search for new recurrent genomic aberrations and patterns, that are potentially important for disease development, disease classification, prognosis, evolution and responsiveness to therapy." "Molecular genetics of early-onset Alzheimer's disease." "Christine Van Broeckhoven" "VIB CMN - Neurodegenerative Brain Diseases Group" "Early-onset Alzheimer's disease (AD) is a fatal neurodegenerative dementia occurring in mid-life (onset of disease between 30 and 65 years) that is severely disruptive for patients and their relatives. An estimated 3000 to 11000 people have early-onset AD in Belgium. Early-onset AD has a strong genetic component, but the majority of the genetic etiology is still unresolved, as mutations in the known dementia genes and the genetic risk conferred by APOE ε4 do not explain more than 10-20% of the occurrence of early-onset AD. The aim of this project is to further unravel the genetic etiology of early-onset AD beyond pathogenic mutations in the known dementia genes by combining a well-documented homogeneous study population with the newest technologies in molecular genetics, to come to a fuller understanding of the pathogenesis of AD. We will employ family-based studies to identify novel pathogenic mutations and rare variants, and we will perform population based whole genome studies to identify potential recessive causes of disease, as well as common genetic risk factors, rare variants and modifying factors. Promising genetic variants will be followed up by functional characterization, genotype-phenotype correlation studies and translation into biomarkers." "Next generation sequencing in molecular genetics for hereditary breast cancer, an emerging new strategy" "Germline BRCA1&2 mutations do not explain a large proportion of the families with hereditary breast cancer. This bilateral research project aims to gain insight in the role of ATM, BRIP1, CHEK2 and PALB2 mutations in Flemish and Québec breast cancer families using the next generation sequencing (NGS) technology. The expertise of both research groups in complementary: the Flemish group will be strongly involved in the development of an effecient genotyping platforms using NGS. A multimodal approach for functional analyses of the variant identified will be developed by the Québec research group." "Molecular Genetics and Biology of Intermediate Charcot-Marie-Tooth neuropathy." "Vincent Timmerman" "Neurogenetics Group, Peripheral Neuropathies Group" "In this FWO apirant mandate we will search for novel mutations in YARS associated with dominant intermediate CMT (DI-CMT), which is essential to make genotype-phenotype correlations. The development of animal models where cellular/tissue dysfunction can be evaluated in an in vivo situation is of crucial importance. Developing such a model in the model organism D. melanogaster will allow us to test the hypothesis on how DI-CMTC is triggered and to screen for genetic and chemical modulators of DI-CMT disease." "Molecular genetics and functional study of HSPB8 mutations associated with hereditary motor neuropathy." "Vincent Timmerman" "Peripheral Neuropathies Group" "In this proposal, I intend to obtain better insights into the precise mechanisms underlying mutant HSPB8 protein resulting in specific neuronal degeneration. Our hypothesis is that distal HMN might be as a result of cell death of peripheral neurons due to aggregation and abnormal interaction of mutant HSPB8 protein. Mutant protein could interfere with the cytoskeleton network and axonal transport pathways, and this could ultimately lead to perikaryal atrophy and axonal loss. Another mechanism might be the impairment of energy production along this specialized axon which might alter axoplasmic transport activities or led to synaptic dysfunction." "Molecular characterization of genetic events driving development of peripheral T cell lymphoma" "Daan Dierickx" "Laboratory of Experimental Hematology, Laboratory of Molecular Biology of Leukemia (VIB-KU Leuven)" "Peripheral T cell lymphoma (PTCL) is a form of blood cancer that develops from mature T cells, a kind of white blood cells. These T cells are growing uncontrollably, thereby forming a tumor that is mostly located in the lymph nodes. PTCL patients are currently treated with chemotherapy, but the chances of survival are only 30%. Therefore, there is a high clinical need for new therapeutic options for these patients. With this research project, we want to investigate the contribution of specific genetic errors that we found in PTCL patients. For this, we will generate these specific genetic errors in mice, so that they will develop T cell lymphomas. We can then use these mice to study the exact mechanisms how these genetic errors drive the development of a lymphoma. We will use this knowledge to identify ways to effectively block the growth of these lymphomas with targeted drugs. Ultimately, we aim to uncover new therapeutic strategies for PTCL patients"