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

• 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
• 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

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.

项目摘要 无症状的腹主动脉瘤（AAA）可能会在院外破裂， 死亡率90%。AAA加速生长与血小板活化和血小板聚集有关。 动脉瘤节段中聚集（血栓）。抗血小板药物可限制AAA生长和破裂 风险对这些观察结果的机械解释从未得到阐明。该项目建立 在我们发现AAA患者的血小板通过选择性表面活化， 受体，抗血小板药物阿司匹林部分抑制AAA的生长和破裂。这 提示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。动脉瘤生长使用离体系统， 在动脉中重现扰动（湍流）血流，定位嗅觉 血小板膜表面的受体是一个新的有希望的抑制AAA的靶点 增长在暴露于湍流血流的AAA患者的血小板中发现这一通路 是我们对血小板如何机械感知和响应的理解的概念性进步 他们的外部环境。因此血小板作为循环生物传感器出现，释放蛋白质 是区分快速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的药物的前景。