Synthetic glycosaminoglycan mimetics as regulators of megakaryopoiesis and thrombopoiesis

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PROJECT SUMMARY Title: Synthetic glycosaminoglycan mimetics as regulators of megakaryopoiesis and thrombopoiesis. Key Words: Platelets, Glycosaminoglycans, thrombopoiesis, G6b-B, NSGMs The Candidate is an NIH K12 postdoctoral scholar on an academic career path. His focus is on the roles of glycosaminoglycans (GAGs) in thrombopoiesis. He has significant research experience studying GAG–protein interactions, and a strong background in organic synthesis notably, the preparation of aromatic-scaffold-based GAG mimetics known as non-saccharide GAG mimetics (NSGMs), which are functional mimics of GAGs. Career Development Plan: This proposal is well structured and involves 2 years of mentored research training, which will ensure that the candidate develops advanced research skills critical for an independent academic career. He has assembled an advisory committee of experienced and well-funded PIs, with proven track records of mentoring young academic researchers. He also has a well-resourced environment for the proposed research. Research Plan: The number of circulating platelets is tightly balanced through continuous production and removal of platelets to prevent potentially detrimental thrombosis. Platelets are produced through sequential processes, wherein hematopoietic stem cells commit to the formation of megakaryocytes (megakaryopoiesis), which release cytoplasmic extensions into the blood stream to produce platelets (thrombopoiesis). While some mechanisms and molecular regulators of these process have been identified, much remains to be elucidated. Of these, the roles of extracellular matrix and GAGs are poorly characterized. Although GAGs are regulators of various proteins, their heterogeneous nature and the challenges associated with obtaining homogeneous forms of these complex biomacromolecules remain bottlenecks for elucidating their biological roles. Our lab has developed a diverse chemical library of NSGMs which possess an aromatic scaffold carrying multiple sulfate groups mimicking the sulfated sugar scaffold of GAGs. NSGMs bind and selectively modulate several GAG- binding proteins involved in diseases, and thus serve as excellent chemical biology probes of GAG function. We have identified G4.1, a flavonoid-based NSGM as having potent thrombopoietic potential in vitro and in vivo. Our preliminary studies show that G4.1 binds with high affinity to G6b-B, an inhibitory receptor found on megakaryocytes and platelets, involved in the regulation of platelet production. Our studies also show that G4.1 promotes G6b-B dimerization, which is required for downstream signaling. Based on this data, we hypothesize that, G4.1 promotes thrombopoiesis, in part, by its highly selective interaction with G6b-B. We will determine the nature of the interaction of G4.1 with G6b-B, probe the selectivity of G4.1 for G6b-B, and elucidate the structure- activity-relationship (SAR) of this class of compounds. This research proposal benefits from; 1) the candidate’s personal track-record, 2) robust preliminary data, 3) a highly experienced advisory committee with relevant expertise to the proposed research, and 4) a supportive and well-resourced research environment. The three aims of the proposal are : I) Determine the nature of interaction of G4.1 with G6b-B, II) Evaluate the selectivity of G4.1 recognition of G6b-B, and III) Synthesize a library of G4.1 analogs and elucidate SAR.