Title Promoter Affiliations Abstract "Molecular characterization of the neuroprotective role of signalling molecules enriched extracellular vesicles" "Joy IROBI" "Immunology - Biochemistry" "One of the most common brain disorders and cause of disability in young adults is the chronic auto-immune disease multiple sclerosis (MS) with worldwide, an estimated 2.5 million people affected. While the numbers of MS patients are strongly increasing, it is unclear how healthcare plans to handle the rising numbers of people affected with MS since there is currently no clear understanding on disease mechanism and thus no effective treatment available that ameliorates the disease. Molecular characterization of innovative prognostic and targeted signaling biomarkers in the pathophysiology is beneficial for the quality of life in MS patients. Furthermore, it also helps to reduce the alarmingly high healthcare costs, caused by the side effects of the non-targeted medication. Therefore, I will perform an investigation to a novel therapeutic strategy by making use of extracellular vesicles as a drug delivery tool to cure MS." "Extracellular vesicles from urine as source of biomarkers for the diagnosis and follow-up of bladder cancer patients." "Inge Mertens" "Center for Oncological Research (CORE)" "Bladder cancer has approximately 2300 new cases in Belgium every year (www.kankerregister.be). Especially in men, bladder cancer is common and is the fourth most common cancer in the world. Nevertheless, the diagnosis of bladder cancer is still not optimal due to the defects of the current standards of urinary cytology and cystoscopy. In addition, the necessary lifelong follow-up makes bladder cancer the most expensive cancer to be treated (Sievert et al., 2009). A non-invasive, cheaper and highly sensitive and specific biomarker set is therefore needed to optimize the diagnosis of bladder cancer on the one hand and to improve the follow-up of low-grade bladder cancer patients on the other. This will improve the quality of life of the patient and decrease the mortality of bladder cancer, the latter through good relapse monitoring, which reduces the risk of metastasis. Exosomes (30-120 nm) are extracellular vesicles (EVs) that are secreted into different body fluids and they contain both RNA, lipids and proteins. They end up in the urine because they are excreted by the epithelia of the urogenital tract. They have enormous diagnostic potential since they play a role in intracellular communication and tumor progression. During the PhD, a method for the purification and characterization of EVs was optimized (results published in JEV). A variant study was performed to determine the interindividual variation at EV protein level. This information has not been known so far, although it is imperative to establish a good discovery experiment capable of identifying an EV protein biomarkers for bladder cancer. The variant study shows that we have to include around 60 samples per experimental group. On the one hand, the urinary EV protein profile of bladder cancer patients will be compared with that of healthy individuals in order to obtain a diagnostic biomarker set. On the other hand, timelines will be established for bladder cancer patients from diagnosis to relapse. By comparing these time points, a biomarker set can be searched for the follow-up of bladder cancer patients. Finally, there will also be a validation study of the potential biomarker sets in a larger population, including patients with other bladder-related pathologies in collaboration with external partners (this validation study is not part of the doctoral work)." "Can the Rnome, encapsulated in extracellular vesicles, assist in directing therapy in patients with metastatic Castration Resistant Prostate Cancer" "Olivier De Wever" "Department of Radiation oncology and experimental cancer research"   "Real-time, label-free analysis of extracellular vesicles and their proteins using surface plasmon resonance technology" "Dominique Schols" "Laboratory of Virology and Chemotherapy (Rega Institute)" "Extracellular vesicles are nanoparticles which are secreted from every cell type in the human body. They convey information between cells by carrying over a variety of molecules from one cell to the other. These molecules and the vesicles themselves vary in composition depending on the type of cell, as well as the type of stress which the cell is exposed to. Cells can carry disease biomarkers which can then also be transferred to the extracellular vesicles. Surface plasmon resonance is a real-time, label-free biosensing technique currently underutilized in the extracellular vesicle research field. By developing a wide array of surface plasmon resonance assays, we plan to distinguish different extracellular vesicles and their proteins in order to identify several diseases (e.g. cancer, viral infections such as HIV and coronaviruses and inflammation) or multiple forms of stress conditions applied to the cells. Consequently, extracellular vesicles production will be investigated as a potential tool for the development of improved viral infection diagnosis and subsequent improved therapeutics." "Investigating the biomarker potential and pathological role of neuronal- and bacterial- derived extracellular vesicles in Parkinson’s disease." "Roosmarijn Vandenbroucke" "Department of Biomedical molecular biology" "Accumulating evidence indicates that extracellular vesicles (EVs) represent a highly interesting biomarker source. Indeed, neuronal-derived EVs (nEVs) separated from peripheral sources provide a snapshot of ongoing pathological changes in the brain whereas bacterial EVs (bEVs) have shown to reflect microbial dysbiosis. Interestingly, both neuronal changes and microbial dysbiosis are evident in Parkinson’s disease (PD) patients. Additionally, EVs are believed to play a role in PD pathogenesis, as it has been shown that nEVs can act as transport vehicles for disease-associated proteins and bEVs can elicit immunomodulatory effects. Here, both the biomarker potential and the pathological role of nEVs and bEVs will be investigated. To explore the biomarker potential, I will analyze size and protein content of nEVs and bEVs separated from plasma, nasal fluid and saliva of PD patients and healthy controls. The biofluids were chosen based on their accessibility, which is of major importance from a biomarker perspective. Additionally, to unravel the role of these nEVs and bEVs in PD pathogenesis, I will identify their recipient cells and validate whether the nEVs and bEVs can accelerate and/or initiate PD-like pathology in in vitro and in vivo models." "PDZ networking in the biology of extracellular vesicles." "Pascale Zimmermann" "Department of Human Genetics, Laboratory for Signal Integration in Cell Fate Decision" "Extracellular vesicles, including exosomes, emerge as organelles governing cell to cell communication.They transport complex information including proteins, lipids and nucleic acids and can reprogramrecipient cells. They participate in the regulation of multiple physio-pathological processes. Yet, themolecular machines governing their production, heterogeneity and activity remain obscure. PDZscaffold proteins organize processes ranging from the plasma membrane to the nucleus and co-evolvedwith multicellularity. Pioneer work and recent findings of our laboratory indicate a role for PDZnetworks in dictating the composition and recapture of extracellular vesicles. Here we propose toanalyze by gain and loss-of-function studies how PDZ webs impact on extracellular vesicle formation,heterogeneity, composition, targeting efficiency and functional effects on recipient cells. We thereby aimfor a better understanding of cell communication and rationale for molecular medicine." "Regulation of intercellular communication via extracellular tumor vesicles generated under the influence of elastokines" "Uwe Himmelreich" "Biomedical MRI" "Pancreatic cancer is currently the fourth leading cause of cancer death in Europe. Pancreatic cancer is a tumor with a very poor prognosis, even if surgery is possible. Pancreatic cancer is characterized by the presence of a transformed microenvironment. This transformed microenvironment involves inflammatory remodelling of the stroma of tissue. This results in accumulation of activated fibroblasts and degradation of the extracellular matrix, in particular elastin fibers. Elastic tissues such as in the lung are one of the most frequent sites for the implantation of metastasis. Elastin is a component of the extracellular matrix and is degraded by proteases during tumor progression. Its degradation leads to the release of elastin-derived peptides (EDPs) also called matrikines. These EDPs are endowed with pro-tumor biological activities that regulate tumor growth and progression by stimulating the activation of proteolytic cascades and stimulating angiogenesis by induction of endothelial cells migration. More recently a new receptor for EDPs identified on the surface of tumor cells: ribosomal protein SA (RPSA). This receptor corresponds to a molecular marker of cancerous aggressiveness present on numerous tumor cells such as pancreatic carcinoma. In addition, these EDPs influence cell mobility by phenotype modification, also called blebbing. Blebbing induced by the interaction of EDPs/RPSA is accompanied by extracellular vesicles release. Extracellular vesicles (EVs) possess many pleiotropic functions by intervening in both physiological and pathological processes such as cancer. The tumor-derived EVs generated under the influence of EDPs can circulate in the blood and thus play a distant role. They serve as a vehicle for transporting and expelling cellular components promoting cellular communication by interacting directly with cells or within the extracellular matrix. They can stimulate tumor growth and be involved in metastatic dissemination by establishing a favorable niche to their implantation. The study of EVs should make it possible to refine the diagnosis especially in the case of tumors localized in tissues rich in elastin and to envisage more targeted treatments. Thanks to novel labelling strategies and novel small animal non-invasive multimodal imaging techniques, it is possible to observe the EVs in vivo. Associated with the in vitro assessment, the aim of this project is to study the regulation of the intercellular communication by tumor-derived EVs generated under the influence of elastokines and to investigated their properties and the mechanisms of action in pancreatic cancer." "Extracellular vesicles as non-invasive biomarkers for assessing the competence of human embryos to implant and establish a clinical pregnancy" "Ann Van Soom" "Department of Human Structure and Repair, Department of Internal Medicine, Reproduction and Population Medicine" "Infertility is a major problem in the human population. Despite significant advances in assisted reproductive technologies, such as in vitro fertilization (IVF), a pregnancy can only be established in 30% of IVF-cycles, as the quality of the embryo plays a major role in initiating the pregnancy. Recently our group has demonstrated the release of microRNAs and extracellular vesicles (EVs) by bovine embryos into the culture medium. We also isolated EVs from medium conditioned by human embryos. MicroRNAs and EVs are important for communication from one cell to another, influencing the translation of genes to proteins and they play a regulating role during biological processes, including pregnancy. We hypothesized that EVs released by a high quality human embryo, which has the potential to create a pregnancy after transfer, differ from EVs released by low grade embryos which do not initiate a pregnancy. Here, we want to extract EVs from culture medium conditioned by human embryos that were selected for embryo transfer. We will provide evidence for internalization of EVs in an endometrial cell line model in response to EVs of implanting and non-implanting embryos. Finally, we will retrospectively compare the contents of EVs isolated from embryos that initiated a pregnancy, with those of embryos that did not induce a pregnancy. As such, we may be able to identify biomarkers for good quality embryos before transfer." "Design and evaluation of a traceable reference material for extracellular vesicles" "Department of Human Structure and Repair, Department of Radiation oncology and experimental cancer research" "The use of a traceable reference material for evaluation of the isolation and characterisation of extracellular vesicles will be evaluated. For this the reference material will be characterized extensively and special attention will be given to resemblances between these particles and endogenous extracellular vesicles. Also different extracellular vesicle isolation methods will be compared and one optimal method will be proposed." "Transient Receptor Potential and Piezo channels as molecular sensors of extracellular lipid vesicles" "Karel Talavera Pérez" "Laboratory of Ion Channel Research (VIB-KU Leuven)" "Transient receptor potential (TRP) and Piezo channels are ubiquitous mechanosensory proteins and are thereby involved in numerous physiological and pathophysiological processes and proposed as targets to treat multiple human diseases. These channels are activated by mechanical stimuli inducing shear stress and changes in membrane curvature and tension, and by the perturbations produced by insertion of chemicals in cell membranes. Based on previous studies by our group and solid preliminary data, we here hypothesize that TRPs and Piezos can sense the extracellular lipid vesicles upon their interaction with the plasma membrane of target cells. We will test this hypothesis by using a wide variety of up-to-date experimental techniques to: 1) screen the effects of natural and artificial lipid vesicles on TRP and Piezo channels, 2) determine the mechanism whereby lipid vesicles activate these channels and 3) determine the pathophysiological relevance of vesicle-channel interactions in somatosensory nerves and epithelial cells. Because TRP and Piezo channels are ubiquitously expressed, the confirmation of our hypothesis will indicate that these channels are universal mediators of the effects of lipid vesicles on target cells, via their key regulatory roles of cellular signaling. Our findings will shed light on the mechanisms underlying the role of extracellular vesicles in intercellular communication and of artificial lipid vesicles used as drug and vaccine vector delivery agents."