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: 10807568
• 负责人: ANDREW J MORRIS
• 金额: --
• 依托单位: CENTRAL ARKANSAS VETERANS HLTHCARE SYS
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10807568
• 关键词: Serum; Amyloid; Critical; mediator; between

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.

急性和慢性炎症对健康不良有很大影响，最显著的是作为 动脉粥样硬化性血管疾病及其并发症的发展，如心肌梗死 脑梗塞/急性冠脉综合征(ACS)、中风和肢体缺血。相关的医疗成本 动脉粥样硬化导致可预防的死亡和严重残疾，这给退伍军人健康带来了压力 护理系统。尽管炎症、动脉粥样硬化性疾病 对于急性冠脉综合征和急性冠脉综合征，治疗策略有限，部分原因是对其机制缺乏了解(S) 炎症刺激血栓形成。他汀类药物治疗降低急性冠脉综合征患者的能力 C反应蛋白升高和Cantos试验的最新结果表明，它可能是 可能通过靶向炎症来预防动脉血栓形成。更好地理解 导致急性血栓形成的炎症信号可以提供更精确的策略 未来的干预措施。在这项建议中，我们提供了急性时相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水平显著升高，急性 炎症和心肌损伤，慢性炎症时略有升高。基于我们的 发现，我们建议的中心假设是，SAA在炎症和 血栓形成。为了验证这一假设，我们召集了一组特殊的退伍军人管理局调查人员 免费赠送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“得到”和“失去”的功能动物模型，其中SAA水平可以被调节 独立于炎症，并遵循不同的炎症挑战。我们将应用这些 用于实现以下两个具体目标的资源：(1)确定SAA在调节中的作用 血小板聚集和血栓形成及其分子机制(S)；(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。的目标是 这笔赠款提供了一种工具，以解决实地尚未解决的一个主要问题，即确定 特异性炎症介质通过影响血小板功能和血栓形成而影响血栓形成 涉及的信号通路。这些结果将是重要的，因为它们预计将提供 创新的靶点，并为可用于预防和治疗的新型抑制剂提供概念验证 人类炎症并发症的治疗。