Title Promoter Affiliations Abstract "Primary muscle degeneration in sporadic Inclusion-Body Myositis: combining deep-proteome data in patient muscle tissue with novel cellular models to pinpoint key mechanisms driving inflammation and aberrant protein expression." "Jonathan Baets" "Translational Neurosciences (TNW)" "Sporadic Inclusion-Body Myositis (sIBM) is the most common myopathy in older adults and has a significant impact on the quality of life; no treatment exists to date. Histopathologically sIBM is characterized by degenerative as well as inflammatory features. In addition to this evident inflammation, striking similarities are observed between sIBM and neurodegenerative diseases. Alternative disease mechanism are suspected since sIBM has no classic genetic cause nor does it respond to immunosuppression as a ""classic"" inflammatory disorder would. Previously we have taken advantage of the availability of disease tissue due to diagnostic muscle biopsies. This allows 'proteomics' studies that capture the entire set of proteins in the diseased muscle and the key 'signatures' of the underlying mechanisms. A total of 61 muscle samples of sIBM-patients and controls were studied. Integrative data-analysis points towards three crucial disease pathways. These are involved in cell growth and repair, DNA damage response and inflammation-control. In the current project we will further study the role of these pathways by performing focused protein expression studies in muscle tissue and through the specific manipulation of these pathways in human-derived myoblast cell-lines in order to reproduce both sIBM pathology and proteomesignature. This novel cell system can be used as a disease model and will aid in the design of disease 'biomarkers' and therapies for sIBM." "A study of the plasmodium vivax reticulocyte invasion pathways and ligan candidates, with special attention to the promising PvTRAg and PvRBP multigenic families." "Cayetano Heredia University, Institute of Tropical Medicine Antwerp (ITM), ADReM Data Lab (ADReM)" "Plasmodium vivax is one of the 5 species causing malaria in humans, and the leading cause of malaria outside Africa. A key step in P. vivax infection is the invasion of reticulocytes (young red blood cells) by the parasite. This invasion is made possible through several interactions between host receptors (reticulocyte membrane) and parasite ligands. While these interactions are well studied for P. falciparum, they remain elusive (and are not comparable) in P. vivax, due to the inability of long-term cultures. However, identifying parasite ligands and characterising the pathways used by the parasite to enter reticulocytes is essential for drug and vaccine development, and is the question that lies at the core of this project. In order to achieve P. vivax elimination, a better understanding of the ligands involved in invasion is necessary. We hypothesize that alternate pathways are used by P. vivax to invade reticulocytes, and that the PvTRAg and PvRBP multigenic families contain important invasion ligands. Therefore, we will carry out the first study integrating newly characterized P. vivax invasion phenotypes with transcriptomic and (epi-)genomic data in field isolates. As such, we expect to advance the knowledge on the role and regulation of PvTrag and PvRBP families in invasion and to discover new potential ligands. Candidate target ligands will be validated by ex vivo invasion assays, and will finally help us to identify the most suited drug and vaccine candidates." "Allele-specific silencing of mutant KCNQ2 as a targeted treatment for KCNQ2 encephalopathy: an in vitro proof of concept study." "Peter De Jonghe" "Neurogenetics Group" "Epilepsy is the forth most common neurological disorder, affecting around 50 million of people worldwide. The epileptic encephalopathies (EEs) are a heterogeneous subgroup of severe epilepsies with onset in the first years of life, which are characterized by treatment resistant seizures and developmental slowing or regression. The majority of EEs have a monogenic basis, and recent advances in gene discovery have greatly increased our neurobiological insights in these disorders. KCNQ2 encephalopathy, caused by mutations in the gene KCNQ2 as described in our research group, is the prototype and most frequent form of EE with neonatal onset. Seizures in these patients often respond poorly to the available anti-epileptic drugs, and more importantly, therapies targeting the neurodevelopmental problems are currently unavailable. In this project we aim to provide evidence for a targeted treatment strategy that has the potential to improve the developmental outcome of these patients. Using neuronal cultures derived of blood cells from patients with KCNQ2 encephalopathy as a disease model, we will study the treatment potential of RNA interference, a biological process that can be exploited to reduce the expression of a disease causing allele. Doing so, we aim to reverse both the epileptic and neurodevelopmental features of EEs. If successful, such an approach can be extended to many more EEs with similar characteristics." "Can we predict rate of cognitive decline in Alzheimer's disease based on genetic modifiers of differential gene expression in the default mode network?" "Kristel Sleegers" "VIB CMN - Neurodegenerative Brain Diseases Group" "Due to increased life expectancy, the number of people suffering from dementia is growing. Alzheimer's disease (AD), the most common form of dementia, is still incurable. Clinical trials with amyloid B (AB plaques as clearing targets have failed to show major improvements, resulting in pharmaceutical companies, such as Pfizer, to reduce investments into AD treatments. This emphasizes that studies on other mechanisms related to underlying pathophysiology of the disease are urgently needed. Moreover, although AB is an early biomarker for AD, it does not have any prognostic value to predict age at onset (AAO) or rate of cognitive decline. We hope to provide proof that altered functional connectivity in the default mode network (DMN), caused by synaptic degeneration, is linked with cognitive decline. This hypothesis will be challenged by studying DMN brain regions with a combined genomics and transcriptomics approach in order to find clear underlying genetic modifiers of altered gene expression. These modifiers will allow construction of a polygenic risk score (PRS) that can predict AAO and rate of decline. Outcomes of this PhD project will provide an insight into the processes contributing to network disruption, possibly delivering new druggable targets as well as prognostic markers for early diagnosis of AD." "Establishment and therapeutic targeting of disease signatures in patient-derived neuronal model of HINT1 neuropathy." "Albena Jordanova" "VIB CMN - Molecular Neurogenomics" "In 2012, our research group reported that HINT1 is associated with Charcot-Marie-Tooth neuropathy (CMT), the most common genetic disorder of the peripheral nerve. The HINT1 enzyme catalyzes the hydrolysis of purine phosphoramidases and all CMT-causing mutations result in a loss of its function. Mutations in HINT1 contribute significantly to the CMT morbidity, however, the physiological role of HINT1 in peripheral neurons and its connection to disease are unclear. In this project, I will create and characterize HINT1 patient-derived motor neurons in order to identify disease-related signatures. To this end, I will make use of transcriptomic profiling, coupled with indepth morphological characterization and functional analyses, including electrophysiological investigations. These findings will allow me to construct the HINT1 regulatory network in neuronal cells. Finally, I will attempt to pharmacologically reverse the identified disease signature(s) in the patient-derived motor neurons to provide proof-of-concept for future therapy development. As a whole, this study will decipher the fundamental role of HINT1 in neuronal homeostasis, will provide mechanistic insights on HINT1-related CMT, and will give tangible clues for designing therapeutic strategies." "Mass cytometry by time-of-flight: next-generation flow cytometry for multiplexed single cell analysis" "Frederik De Smet" "Translational Cell & Tissue Research, Therapeutic and Diagnostic Antibodies, Centre for Molecular and Vascular Biology, Clinical and Experimental Endocrinology, Laboratory for the Research of Neurodegenerative Diseases (VIB-KU Leuven), Molecular Digestive Oncology, Laboratory of Angiogenesis and Vascular Metabolism (VIB-KU Leuven), Laboratory for Neuroimmunology, Research Group Experimental Neurosurgery and Neuroanatomy, Tracheal Transplantation, Laboratory for Disease Mechanisms in Cancer, Laboratory for Molecular Neurobiomarker Research, Stem Cell and Developmental Biology, Laboratory of Tumor Inflammation and Angiogenesis (VIB-KU Leuven), Adaptive Immunology, Laboratory for Molecular Cancer Biology (VIB-KU Leuven), Translational Research in GastroIntestinal Disorders, Switch Laboratory (VIB-KU Leuven), Laboratory of Glia Biology (VIB-KU Leuven)" "Describing every single cell in the human body is one of the greatest challenges of our era. Single-cell technologies aim at mapping multiple properties of millions of single cells, both in health and disease. Flow cytometry is still the most important tool for single cell, targeted, protein-based analysis. However, standard fluorescence-based cytometry, which commonly measures 300 researchers across KU Leuven with access to state-of-the-art single cell technology." "Single-cell omics in high throughput and at spatial resolution" "Thierry Voet" "Stem Cell and Developmental Biology, Laboratory of Glia Biology (VIB-KU Leuven), Laboratory for Molecular Cancer Biology (VIB-KU Leuven), Research Group Molecular Neurobiology (VIB-KU Leuven), Laboratory for Disease Mechanisms in Cancer, Gynaecological Oncology, Laboratory of Computational Biology (VIB-KU Leuven), Laboratory of Translational Genetics (VIB-KU Leuven), Woman and Child, Laboratory for the Research of Neurodegenerative Diseases (VIB-KU Leuven), Department of Human Genetics" "A human body comprises 10 to 100 billion cells (= 10 to 100 x 1000.000.000.000 cells). As most of our organ functions are executed by the concerted action of those individual cells in a spatially organised context, it is paramount to research individual cells in their native spatial context. This is not only important to understand normal organ development and function, but also to investigate how (subpopulations of) cells are perturbed in diseased conditions as cancer or neurological disorders. This proposal will establish a fourth-generation sequencing device that preserves the spatial coordinates of RNA and DNA sequences within tissue sections with up to subcellular resolution, thus enabling localizing sequencing reads within single cells in their original histological tissue context. Apart from in situ sequencing technology, the same device will also enable the detection and visualisation of transcripts from 100s to 1000s of genes within single cells at unprecedented accuracy and with spatial inter- and intracellular information. Accessories will enable interrogating single cell DNA and RNA in high throughput and spur further method development for the analysis of single cells. Approaches for single-cell sequence analysis are revolutionizing our understanding of the extent, nature and biology of cellular diversity that occurs in the lifetime of an organism in health and disease. " "Exploring the role of kinases and phosphatases in Charcot-Marie-Tooth neuropathy." "Maria-Luise Petrovic-Erfurth" "VIB CMN - Molecular Neurogenomics" "Peripheral neuropathies (PNs) affect 3-4% of the old (>55 years). Often, the disease manifests as result of stress (e.g. diabetes or chemotherapy). There are also hereditary forms of neuropathies. Patients experience altered sensations and pain in hands/feet as well as orthopedic and coordination problems. Hereditary PNs start in the first two decades of life. Among them Charcot- Marie Tooth disease (CMT) is the most frequent subtype which is currently, like all other PNs, incurable. Patients are only treated to relieve symptoms, leaving them ultimately severely disabled. The development of a therapy, requires a better understanding of the molecular mechanisms underlying CMT. I propose to test the role of a regulatory cellular signaling mechanisms (phosphorylation) in the CMT-etiology. As an expert in the biology of neuropathy and phosphorylation, I will perform my work in a lab specialized in CMT-genetics. My idea that phosphorylation might be critical for CMT results from a genetic screen utilizing the CMT-fly model established by my host lab. To verify these results, I have engineered human CMT-cell lines. By analyzing their signaling state via (phosphor)- proteomics, I will pinpoint the best molecular targets for future therapies. The advantage of focusing on phosphorylation is the detailed knowledge of phosphor-pathways and their modulators. I will genetically test putative drug-targets in vivo laying the foundation for the first therapy specific for CMT. -" "Understanding reduced penetrance of ABCA7 premature termination codon mutations in Alzheimer's disease." "Kristel Sleegers" "VIB CMN - Genetics of Alzheimer’s Disease, VIB CMN - Neurodegenerative Brain Diseases Group" "Evidence accumulates that predicted loss-of-function mutations in the Alzheimer risk gene ABCA7 are 4 — 5 times more frequent among Alzheimer's disease (AD) patients than cognitively healthy individuals. Two striking characteristics of ABCA7 mutation carriers are -on the one hand- an increased proportion of familial disease, and -on the other hand- wide spread in onset age and incomplete penetrance. Thus, while these mutations might be clinically relevant given their relatively high frequency and significant effect on personal as well as familial disease risk, reduced penetrance currently hinders implementation of genetic screening for ABCA7 mutations in clinical practice. In a pilot experiment using third generation cDNA sequencing, we identified potential rescue mechanisms at transcript level that may explain reduced penetrance of these mutations. Here, we propose to perform long-read cDNA sequencing analyses on different tissues of a large series of mutation carriers, and correlate mutation-rescue events with parameters of disease severity. We have an unprecedented repository containing 104 ABCA7 PTC mutation carriers, putting us in a unique position to conduct this project. The outcomes of this project will be important for informed decision making on diagnostic screening of ABCA7 in AD. The insights gained through nature's own rescue experiments at transcript level will provide a window onto pharmaceutical intervention strategies for this genetic subtype of AD." "Dissection of the AnkyrinG interactome." "Frank Kooy" "Cognitive Genetics (COGNET)" "While the introduction of next generation sequencing led to a breakthrough in the discovery of novel genes responsible for neurodevelopmental disorders, most notably intellectual disability and autism, our understanding of the underlying disease causing pathology is lagging behind, in part due to the extreme genetic heterogeneity. Despite substantial in silico evidence that many diseases genes responsible for neurodevelopmental disorders cluster in a relatively limited number of protein protein interaction (PPI) networks, no experimental work on the subtle phenotypical effects that disturbances of such a network may cause has been reported to our knowledge. In this application, we therefore zoom in for the first time on the effects of the combined genetic variation present in an entire PPI network, rather than on the effect of mutations in single genes. We selected the AnkyrinG interactome, as it is a well-defined interaction network that is strongly connected with multiple neurodevelopmental disorders. By a detailed characterization of the genetic variation present in the AnkyrinG interactome in a large patient cohort, in combination with transcriptomics, proteomics and validation studies, we want to define the role of this PPI network as a unifying factor in neurodevelopmental disorders."