Andrew Leavitt, MD

Hematopoiesis is a life-long developmental process requiring maintenance of a precursor/stem cell pool, generation of adequate numbers of circulating mature blood cells, and the ability to individually modulate each developmental lineage in response to specific needs of the organism. My lab uses murine models to study megakaryocytopoiesis, the “branch” of hematopoiesis that produces circulating platelets. We are currently studying the role of the Raf family, especially Raf-1 and B-Raf, and Stat-5 signaling in megakaryocytopoiesis.

Platelets play a critical role in clot formation through the binding of fibrinogen by their surface integrin aIIbb3. The aIIbb3 on resting, circulating platelets is unable to bind fibrinogen until the platelet is activated by one or more platelet agonists, typically at the site of vascular injury. The activation of aIIbb3 results in increased affinity and avidity of aIIbb3 for its ligand and is called agonist-induced “inside-out” signaling. We have demonstrated that inside-out signaling is developmentally regulated during megakaryocytopoiesis and that megakaryocytes lacking the transcription factor NF-E2 fail to undergo agonist induced aIIbb3 inside-out activation. We are currently using various methods of differential expression analysis to identify the NF-E2 regulated genes that play a role in the aIIbb3 inside-out signaling. These gene products should provide useful targets for new classes of anti-platelet agents.