Secretion from platelets is a critical process required for correct hemostasis. While several studies have shown that SNARE proteins are required for platelet secretion, little is understood about how they are regulated upon platelet activation. Nonetheless, we have previously identified the IKK pathway as a key regulator of platelet SNARE-dependent secretion. And subsequently shown that the scaffolding protein MALT1 is ubiquitinated and regulates IKK activity, and SNARE complex formation, in platelets. Thus, we hypothesize that IKK and upstream signaling molecules are present in platelets and play an important role in platelet exocytosis, and the genesis of thrombosis. We further hypothesize that proteasome/PSMC1 plays an important role in NF-?B/IKK signaling in platelet and in thrombogenesis. The following Aims are designed to test our hypothesis:
Specific Aim I : Delineate the signaling elements that are upstream of IKK activation and assess the biochemical ramification of IKK activation and regulation of SNARE complex formation in stimulated platelets.
Specific Aim II : Investigate the function of the proteasome/PSMC1 in platelet activation and thrombogenesis. To accomplish these translationally-relevant aims, we will employ a host of biochemical, genetic and pharmacological tools and approaches, with the ultimate goal of defining new therapeutic agents and/or novel targets for the management of thrombotic disorders.
Collectively, the experiments presented in this application, some of which are translational in nature, address fundamental and mechanistic concerns regarding the platelet granule secretion responses, in the context of IKK and the proteasome/PSMC1. Results obtained from these studies should lay down the foundation for understanding, and developing novel agents and means for the therapeutic management of thrombosis-based disease states.