Serum Amyloid as a Critical mediator between inflammation and thrombosis

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Acute and chronic inflammation contributes significantly to poor health, most notably as a risk factor for the development of atherosclerotic vascular disease and its complications, such as myocardial infarction/acute coronary syndromes (ACS), strokes, and limb ischemia. The medical costs associated with atherosclerosis contribute to preventable death and serious disability, which strain the VA health care system. Despite the well-established relationship between inflammation, atherosclerotic disease and ACS, treatment strategies are limited, due in part to a lack of understanding of the mechanism(s) by which inflammation stimulates thrombosis. The ability of statin therapy to lower ACS in patients with elevated C-reactive protein and the recent results from the CANTOS trial suggest that it may be possible to prevent arterial thrombosis by targeting inflammation. A better understanding of the inflammatory signals that contribute to acute thrombosis could provide a more precise strategy for future interventions. In this proposal, we provide evidence that the acute phase reactant serum amyloid A (SAA) has direct effects on platelet function. SAA levels increase dramatically with acute inflammation and myocardial injury and are modestly elevated with chronic inflammation. Based on our findings, we suggest the central hypothesis that SAA serves as a key link between inflammation and thrombosis. To test this hypothesis, we have assembled an exceptional group of VA investigators with complimentary expertise in inflammation and thrombosis and unique model systems and reagents. Importantly, we have “gain” and “loss” of function animal models in which SAA levels can be modulated independent of inflammation and following different inflammatory challenges. We will apply these resources to accomplish the following two specific aims: (1) to identify the role of SAA in modulating platelet aggregation and thrombosis and the molecular mechanism(s) involved and (2) to elucidate the role of SAA in promoting platelet secretion and leukocyte interactions during inflammation. The aims of this grant provide a vehicle to address a major unresolved issue in the field, namely identification of specific inflammatory mediators that influence thrombosis through effects on platelet function and the signaling pathways involved. These results will be significant, because they are expected to provide innovative targets and provide proof-of-concept for novel inhibitors that may be used for prevention and treatment for the complications of inflammation in humans.