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状况不佳有很大影响，最明显的是作为一个危险因素， 动脉粥样硬化性血管疾病及其并发症的发展，如心肌 梗塞/急性冠状动脉综合征（ACS）、中风和肢体缺血。相关的医疗费用 与动脉粥样硬化有助于可预防的死亡和严重残疾，应变VA健康 护理系统。尽管炎症、动脉粥样硬化性疾病 和ACS，治疗策略有限，部分原因是缺乏对机制的理解 炎症刺激血栓形成。他汀类药物治疗降低ACS患者的能力 C反应蛋白升高和CANTOS试验的最新结果表明， 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。在这个建议中，我们提供的证据表明，急性期反应物血清淀粉样蛋白 SAA对血小板功能有直接影响。SAA水平随着急性 炎症和心肌损伤，并且随着慢性炎症适度升高。基于我们 研究结果，我们提出了中心假设，即SAA是炎症和炎症之间的关键联系， 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事务部调查人员， 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，我们有功能“获得”和“丧失”的动物模型，其中SAA水平可以调节 独立于炎症并且遵循不同的炎症挑战。我们将应用这些 （1）确定SAA在调节 血小板聚集和血栓形成及其分子机制;（2）阐明 SAA在炎症期间促进血小板分泌和白细胞相互作用中的作用。的目的 这笔赠款为解决外地一个尚未解决的主要问题提供了一个手段， 特异性炎症介质通过对血小板功能的作用影响血栓形成， 信号通路参与。这些结果将是重要的，因为它们预计将提供 创新的目标，并提供概念验证的新型抑制剂，可用于预防和 治疗人类炎症并发症。