research 60 research 61 OLIVIER DETRY Role of Mesenchymal Stromal Cells (MSC) during Normothermic Machine Perfusion (NMP) of kidney grafts from donation after circulatory death (DCD) Organ transplantation is a victim of its own success, with increasing numbers of medical indications and potential transplant candidates, and a critical shortage of deceased donors. This situation has led to the development of living donor techniques or the use of high-risk grafts, such as from elderly donors or even from Donation after Circulatory Death (DCD), particularly in Belgium. Cold static preservation, the current standard for abdominal organ preservation, insufficiently preserves these high-risk grafts as they are more vulnerable to ischemia-reperfusion injury (IRI), with higher rates of graft loss due to dysfunction or non-function. The main objective of this project is to test the hypothesis that the infusion of DCD kidney grafts with Mesenchymal Stromal Cells (MSCs) improves the perfusion and function of these grafts by reducing IRI. This hypothesis will be tested in 2 preclinical models of normothermic machine perfusion (NMP), first using a porcine DCD model, and then human DCD grafts rejected for clinical transplantation. Each kidney perfused with MSCs (MSC group) will be compared to the contralateral kidney not receiving MSCs (control group). These results will be confirmed in a swine model of renal autotransplantation. KRISTEL VAN STEEN Expanded PRS embracing pathways and interactions for increased clinical utility A polygenic risk score (PRS) is a number that summarizes the estimated effect of many genetic variants on an individual’s phenotype, typically derived from weights from cross-sectional genome-wide association studies (GWASs) of prevalent disease cases and controls. Clinical implementation of PRS may help inform diagnostics or treatment choices. Higher-end extreme PRS scores for some diseases can approximate risks equivalent to those embodied by clinical risk factors or monogenic disorders. However, more work is needed to increase the discriminative power of PRS in a general population, estimate lifetime risk trajectories, or identify fine-scale substructure in patient populations. This project combines disease knowledge-informed molecular interaction networks with GWAS-induced large-scale epistasis screening to derive novel expanded pathway-PRSs. The outcome is a newly developed composite score composed of 1- and 2-dimensional genetic information and an optimization protocol according to prediction performance and disease subtyping. As a by-product, the project will provide insights into the added value of pathway-oriented epistasis screening and handling complex genetic risk regions.
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