Fellowship for Michael Chicka: Unveiling the Molecular Mechanisms Underlyung Ca2+-triggered Platelet Secretion

Platelets respond to vascular damage and initiate many of the responses required for hemostasis. While platelet function is necessary in organisms with an enclosed vasculature, hyperactive platelets can induce aputious thrombosis that is linked to heart attacks and swokes Therefore mechanisms mutt be in place to regulate platelet function- Cenbal to platelet activation is the release of cargo from three secretory granule stores; dents core granules, alpha- granules and lyaoaomes. Collectively cargo accelerates thrombosis by enhanctng platelet recruitment and adhesion, and by trtggering tIle formation of fLbrln network fhst serves as a base for clot formaton, Ttius. platelet sworation las at the junction between platelet function and dysfunction- The goats of Aims 1 and 2 proposed hera are to define the molecular mechanisms that mediate and regulate secretion in order to reveal ways of modulating platelat furlct!~SNARE proteins directly catalyza secrettn by pairing with each other. ht~Vlbvsr, of the 48 possible SNARE combinations in platelets, little is knowi about their individual roles or about which SNARE combinations - function during secretion, We hypothesize that SNARE prolsin ctmbinationa differentially mediste fusion and ere the dominent factors in conveying apactfidty to ptatetet secratton. We will use a reconstituted membrane fusion essay to determine directly which platelet SNARE combtnationa euppoti intembrane fusion and shed tight onto SNAnm usagelrolaa in platelets Secraaon is also tghtly regulated by acceasory proteins- MuncIff and taluncis.