Inherited Platelet Function Disorders

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Research Synopsis

Inherited platelet function disorders
Platelets are small, numerous blood cells that initiate and co-ordinate blood clotting at wound sites, where they adhere, secrete an assortment of molecules and support progression of the “coagulation cascade.” Platelets are also involved in the formation of arterial plaques and pathological clots, such as the arterial thrombi that cause heart attacks and strokes (both major causes of mortality in the modern world). Research in my laboratory is focused on advancing our understanding of platelet biology by studying inherited platelet disorders. For example a recent investigation into a severe disorder (ARC Syndrome) led us to identify a protein, VPS33B, involved in the formation of platelet alpha granules in their cellular precursors, megakaryocytes. Understanding the mechanisms of VPS33B-mediated platelet alpha granule formation is a current focus in my laboratory.

VPS33B is a 617 amino acid 70.6 kDa protein expressed in numerous tissues that is associated with late endosomes/lysosomes in cells. As a member of the Sec1/Munc18 protein family, VPS33B is predicted to interact with SNAREs to facilitate docking and fusion of intracellular vesicles. Efforts are underway to identify potential VPS33B binding proteins. Candidate proteins are currently being evaluated using a combination of molecular, cellular and biochemical approaches. RNAi techniques are being utilized to evaluate the loss of VPS33B function in human megakaryocytes. Candidate VPS33B binding proteins are also being knocked down using RNAi to assess their role during alpha granule biogenesis.

There are a number of collaborative studies ongoing in my laboratory. One area of research is investigating the role of the complement system and platelets in the pathogenesis of atypical hemolytic uremic syndrome (HUS). Another is investigating the recently discovered biosynthetic ability of platelets in health and disease. We are also investigating the role of myosin IIA function in platelets and megakaryocytes by examining a cohort of children with MYH9-related macrothrombocytopenia.