Serum Amyloid as a Critical mediator between inflammation and thrombosis

血清淀粉样蛋白是炎症和血栓形成之间的关键介质

• 批准号: 9888883
• 负责人: Susan S. Smyth
• 金额: --
• 依托单位: VA MEDICAL CENTER - LEXINGTON, KY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9888883
• 关键词: Acute; Acute myocardial infarction; Acute-Phase Proteins; Address; Adhesives; Agonist; Amyloid; Animal Model; Arterial Injury; Atherosclerosis; Biochemical; Biological Models; Biology; Blood Platelets; C-reactive protein; Cardiovascular Diseases; Cardiovascular system; Chronic; Clinical Trials; Collaborations; Cues; Data; Development; Diagnosis; Event; Experimental Models; Future; Genetic; Goals; Grant; Health; Healthcare Systems; Hemostatic function; Human; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Intervention; Knowledge; Leukocytes; Link; Literature; Mediating; Mediator of activation protein; Medical Care Costs; Molecular; Morbidity - disease rate; Mus; Myocardial Infarction; P-Selectin; Pathologic; Pathway interactions; Patients; Pharmacology; Physiological; Plasma; Platelet Activation; Platelet aggregation; Play; Pre-Clinical Model; Prevention; Reagent; Research; Research Personnel; Resources; Risk Factors; Role; Serum; Serum amyloid A protein; Signal Pathway; Signal Transduction; Stroke; Techniques; Testing; Thrombosis; Veterans; Work; acute coronary syndrome; base; disability; improved; inhibitor/antagonist; innovation; limb ischemia; loss of function; mortality; myocardial injury; novel; overexpression; platelet function; preclinical study; prevent; preventable death; response; response to injury; synergism; thromboinflammation; tissue injury; treatment strategy; vascular injury

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.

急性和慢性炎症是导致健康状况不佳的重要因素，最明显的是作为一种风险因素