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.

急性和慢性炎症会严重影响健康状况，最值得注意的是，它是以下疾病的危险因素： 动脉粥样硬化性血管疾病及其并发症的发展，例如心肌 梗塞/急性冠脉综合征 (ACS)、中风和肢体缺血相关的医疗费用。 动脉粥样硬化导致可预防的死亡和严重残疾，这给退伍军人管理局的健康造成压力 尽管炎症与动脉粥样硬化疾病之间存在明确的关系。 和 ACS，治疗策略有限，部分原因是缺乏对机制的了解 他汀类药物治疗通过炎症刺激血栓形成来降低 ACS 患者的能力。 C 反应蛋白升高和 CANTOS 试验的最新结果表明，这可能是 可以通过针对炎症来预防动脉血栓形成。 导致急性血栓形成的炎症信号可以提供更精确的策略 在此建议中，我们提供了急性期反应物血清淀粉样蛋白的证据。 A (SAA) 对血小板功能有直接影响，SAA 水平在急性发作时急剧增加。 根据我们的研究，炎症和心肌损伤会随着慢性炎症而适度升高。 研究结果表明，我们提出了一个中心假设：SAA 是炎症和炎症之间的关键联系。 为了检验这一假设，我们召集了一组特殊的 VA 研究人员 炎症和血栓形成方面的专业知识以及独特的模型系统和试剂。 重要的是，我们有“获得”和“丧失”功能的动物模型，其中 SAA 水平可以调节 独立于炎症并遵循不同的炎症挑战我们将应用这些。 资源来实现以下两个具体目标：（1）确定 SAA 在调节中的作用 血小板聚集和血栓形成以及所涉及的分子机制（2）阐明 SAA 在炎症过程中促进血小板分泌和白细胞相互作用的作用。 这笔赠款提供了一个工具来解决该领域尚未解决的一个重大问题，即查明 特定的炎症介质通过影响血小板功能和血小板功能来影响血栓形成 这些结果将是重要的，因为它们有望提供。 创新目标并为可用于预防和治疗的新型抑制剂提供概念验证 治疗人类炎症并发症。