Platelets as Biosensors and Mediators of Aortic Aneurysm Growth

血小板作为主动脉瘤生长的生物传感器和介质

基本信息

批准号：
10434958
负责人：
Scott James Cameron
金额：
$ 51.28万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10434958
关键词：
Abdomen Abdominal Aortic Aneurysm Affect American Aneurysm Antiplatelet Drugs Aorta Aortic Aneurysm Arteries Aspirin Biological Markers Biomechanics Biosensor Blood Blood Cells Blood Circulation Blood Platelets Blood Vessels Blood flow Cardiovascular Diseases Cause of Death Cessation of life Chronic Clinical Trials Communication Communities Coronary Arteriosclerosis Country Data Development Disease Elderly Emergency Situation Endopeptidases Engineering Environment Enzymes Event Exposure to Glycoproteins Goals Growth Health Care Costs Hospital Mortality Intervention Laboratories Life Ligands Link Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Mechanics Mediator of activation protein Medical Membrane Membrane Proteins Mus Operative Surgical Procedures Pathogenesis Pathway interactions Patients Peripheral Peripheral arterial disease Pharmaceutical Preparations Pharmacologic Substance Plasma Platelet Activation Platelet aggregation Proteins Research Personnel Risk Rupture Ruptured Abdominal Aortic Aneurysm Ruptured Aneurysm Surface Swelling System Testing Therapeutic Thrombus Time Tissue Inhibitor of Metalloproteinase-1 Tissue Inhibitor of Metalloproteinases Tissues United States Zinc antagonist base career cerebrovascular cohort comorbidity cost extracellular human old age (65+)insight men mouse model novel olfactory receptor platelet phenotype protein expression receptor surgical risk thrombotic transcriptomics

项目摘要

Project Summary Asymptomatic abdominal aortic aneurysms (AAA) can progress to rupture with an out-of-hospital mortality of 90%. Accelerated AAA growth is associated with platelet activation and platelet aggregates (thrombi) in aneurysmal segments. Antiplatelet drugs may limit AAA growth and rupture risk. A mechanistic explanation for these observations has never been elucidated. This project builds upon our discovery that platelets from patients with AAA are hyperactivated through selective surface receptors and that the antiplatelet drug aspirin partially inhibits AAA growth and rupture. This suggests a new link between platelet activation and aneurysm development, and implies aspirin may not be the best antiplatelet drug to suppress. aneurysm growth. Using an ex vivo system to recapitulate disturbed (turbulent) blood flow in aneurysmal arteries, localization of an olfactory receptor on the surface of the platelet membrane is a new and promising target to suppresses AAA growth. Discovering this pathway in platelets from patients with AAA exposed to turbulent blood flow is a conceptual advancement in our understanding of how platelets mechanically sense and respond to their external environment. Platelets therefore emerge as circulating biosensors, releasing proteins that are useful biomarkers for distinguishing fast from slow-growing aneurysms. This project offers the promise of the first medical therapy to treat AAA.

项目概要无症状的腹主动脉瘤 (AAA) 可能会因院外治疗而进展至破裂死亡率90%。加速 AAA 生长与血小板活化和血小板相关动脉瘤部分聚集（血栓）。抗血小板药物可能会限制 AAA 的生长和破裂风险。这些观察结果的机械解释从未被阐明。本项目构建我们发现 AAA 患者的血小板通过选择性表面过度活化受体，抗血小板药物阿司匹林部分抑制 AAA 生长和破裂。这表明血小板活化和动脉瘤发展之间存在新的联系，并暗示阿司匹林可能不是最好的抗血小板药物来抑制。动脉瘤生长。使用离体系统概括动脉瘤动脉中受干扰（湍流）的血流，嗅觉的定位血小板膜表面的受体是抑制 AAA 的一个新的、有前景的靶点生长。在暴露于湍流血流的 AAA 患者血小板中发现这一通路是我们对血小板如何机械感知和反应的理解的概念性进步他们的外部环境。因此，血小板成为循环生物传感器，释放蛋白质它们是区分快速生长和缓慢生长的动脉瘤的有用生物标志物。该项目提供第一种治疗 AAA 的药物疗法的承诺。