Isabel Rosa

Supervisor: Professor Willem Ouwehand

Title: Exploring the molecular basis underlying the observed effect of the silencing of BRD3 on platelet formation with the purpose to identify possible epigenome-modifying therapeutic interventions

Abstract: Platelets play an important role in maintaining haemostasis and vascular health.  Drugs that inhibit platelets' pro-thrombotic function are the corner stone of the treatment of patients with acute coronary syndrome and after myocardial infarction (MI).  Unfortunately, the use of triple antiplatelet therapy causes severe bleeding in a large fraction of patients, limiting standard care to aspirin and clopidogrel with ReoPro being used for high-risk cases only. Therefore there is a need to explore an alternative class of therapeutic compounds for modulating the functional characteristics of myeloid blood cells, including platelets. Platelets are formed by the largest progenitor cell in the bone marrow, the megakaryocyte (MK).

GWAS has identified new regulators of megakaryopoiesis. Our meta-analysis of GWAS in nearly 68,000 individuals identified nearly 20 genes coding for DNA or chromatin binding protein, including transcription factors, acetylases, methylases and other chromatin modifiers.  One of the genes from the latter group is BRD3. It has been implicated in the formation of myeloid blood cells and if mutated can cause myeloid leukaemia’s. Moreover, zebrafish ortholog of BRD3 is the rate-limiting regulator of thrombocyte (zebrafish platelet homologs) formation.

My PhD project will include 1) conditional knockout mouse models to analyse the role of Brd3 in megakaryopoiesis and the formation and function of platelets, 2) stem cell biology and mass spectrometry to identify BRD3 interactors, and 3) human genomics to study the effect of rare coding variants on platelet phenotypes in large populations.  The overall purpose of my PhD project is to obtain a better understanding of the function of BRD3 in myelopoiesis and especially megakaryopoiesis with the purpose to use BRD3 inhibitors into proof-of-principle studies.

Exploring the molecular basis underlying the observed effect of the silencing of the GWAS gene BRD3 on platelet formation with the purpose to identify possible epigenome-modifying therapeutic interventions

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