Grants and Contracts Details


Ischemia, caused by spurious thrombosis, accounts for 1 in 4 non-communicable disease deaths, world-wide. Normally platelets respond to vascular damage and secrete a plethora of granule cargo that are essential for recruiting more platelets, their adhesion, and consequent thrombosis. This releasate promotes normal sequelae but can also contribute to disease. Do platelets actively control what they release or are they indiscriminant delivery devices? The answer shapes our understanding of how platelets affect the vascular microenvironment. We, and others, have shown that membrane proteins (v- and t-SNAREs) fuse granule and plasma membranes to allow cargo release. In platelets, VAMPs, SNAP-23, and Syntaxin-11 form a membrane-spanning complex that mediates fusion. Complex formation requires both post-translational modifications and a host of SNARE-regulators. This regulation affects the complexity of the platelet release reaction: controlling its rate, extent, and perhaps content. We hypothesize that the platelet secretory machinery is a viable target to modulate thrombosis with only modest effects on hemostasis. We propose three Aims: 1) Define the extent of platelet secretion heterogeneity and its effects on hemostasis and thrombosis. Using kinetic experiments and agonist titrations, we will define platelet secretion heterogeneity. We will also genetically titrate the secretory machinery to determine how thrombosis and hemostasis is influenced when secretion is altered. 2) Define the mechanisms by which enzymatic, post-translational modifications of SNAREs modulate platelet exocytosis. We will alter the dynamic acylation of Syntaxin-11 and SNAP-23 with acyltransferase and thioesterase inhibitors to define how this modification affects secretion. SNAP-23 is also phosphorylated by IêB kinase (IKK). We will determine the role of that modification and whether IKK inhibitors can be used to affect thrombosis. 3) Identify and define new elements of the molecular machinery required for platelet exocytosis. We will probe the roles of two new secretory elements, á-synuclein and RalA/B, to determine how they affect hemostasis. The proposed studies expand our knowledge of the molecular requirements and the sequence of protein-protein interactions controlling platelet exocytosis. In sum, the work is significant at the clinical level since our data are vital to interpreting the correlations identified by from Precision Medicine Initiatives and Genome-Wide Association Studies of thrombotic risk factors. The mechanistic understanding generated by our studies is essential as we seek to evaluate the physiological relevance of these gene/risk associations.
Effective start/end date7/1/963/31/20


  • National Heart Lung and Blood Institute: $1,341,679.00


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