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Project

Pathophysiological characterization of megakaryopoiesis and platelet production: omics for thrombocytopenia and functional studies.

Platelets, the 2nd most abundant cell in the blood, play a pivotal role in cardiovascular diseases. The number, volume and function of platelets vary widely in the healthy population and are highly heritable. Genome-wide association studies have delivered information on common sequence variation in known but also novel genes that control these 3 traits. On the other end of the spectrum of sequence variation, known and hitherto not yet defined “very rare variants” cause aberrant platelet phenotypes that are associated with bleeding. By studying the etiology, molecular biology and pathophysiology of inherited platelet disorders (IPDs), DNA variants, genes and pathways will be discovered that place pointers at new regulators of the formation, function and survival of platelets. This project will specifically focus on IPDs with defects in megakaryopoiesis and/or platelet formation (thrombocytopenia). With the advent of next generation sequencing it is now possible and affordable to discover a large fraction of the causative variants not yet defined and this technique will be used to exome sequence 35 unrelated patients with thrombocytopenia for which known causes have been excluded. System biology approaches are next essential to study the exact role of these novel candidates and some other known regulators with a yet however undefined function (as for exon junction complex member Y14) during megakaryopoiesis. For that purpose, we will use functional genetics in zebrafish and in vitro megakaryocyte differentiation assays starting from peripheral blood-derived hematopoietic stem cells or inducible pluripotent stem cells obtained from patients’ fibroblasts. This study is expected to gain important insights in the poorly understood and complex process of megakaryopoiesis for also improved diagnosis and treatment of IPDs.

Date:1 Jan 2013 →  31 Dec 2016
Keywords:Megakaryopoïese, Bloedplaatjesproduktie, Trombocytopenie
Disciplines:Cardiac and vascular medicine