Mechanisms of Thrombus Instability

血栓不稳定的机制

• 批准号: 6707461
• 负责人: DAVID J LOSKUTOFF
• 金额: $ 46.93万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-05 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6707461
• 关键词: autoradiography; biological signal transduction; blood vessels; bone marrow transplantation; clinical research; disease /disorder model; electron microscopy; enzyme linked immunosorbent assay; human tissue; immunocytochemistry; in situ hybridization; laboratory mouse; leptin; obesity; platelet activation; platelet aggregation; platelets; polymerase chain reaction; thrombosis; western blottings

DESCRIPTION (provided by applicant): Thromboembolic disease is a major cause of sudden death and catastrophic disability in Western societies. This grant will employ murine models of obesity to delineate underlying mechanisms. Preliminary Studies indicate that thrombi formed in ob/ob (leptin-deficient) and db/db (functional leptin receptor-deficient) mice in response to arterial injury (FeCI3) are unstable and frequently embolize. Administration of leptin stabilizes the thrombi formed in ob/ob but not in db/db mice, and promotes the aggregation of platelets from ob/ob but not db/db mice. The primary hypothesis of this grant is that leptin binds to its receptors on platelets, causing biochemical changes in platelet signaling and function that are necessary for thrombus stability. In Aim 1, bone marrow transplantation studies and leptin and leptin inhibitor (e.g., neutralizing antibodies) infusion studies, will be performed to determine the origin, target, and kinetics of action of the stabilizing leptin in thrombi, and to test the hypothesis that decrease in leptin will lead to the formation of unstable thrombi in wild-type mice. The mechanism(s) by which leptin promotes thrombus stability and enhances platelet activation will be studied in Aim 2. The possibility that leptin is required for optimal platelet: platelet and/or platelet vessel wall interactions will be examined, and the effects of leptin and leptin inhibitors on the aggregation, secretion and signaling of murine platelets will be determined. Preliminary Studies show that leptin potentiates the aggregation of human platelets from some donors but not from others. In Aim 3, the nature of the defect in non-responsive platelets (e.g., abnormalities in the leptin receptor) will be examined. The effects of leptin inhibitors on the aggregation of responsive and non-responsive platelets, and on the formation of stable "thrombi" will be tested. These studies will provide novel insights into the unexpected role of leptin in platelet function, and in the formation and stability of thrombi.

描述（由申请人提供）：血栓栓塞性疾病是西方社会猝死和灾难性残疾的主要原因。该基金将采用小鼠肥胖模型来描述潜在的机制。初步研究表明，响应于动脉损伤（FeCl 3）在ob/ob（瘦素缺陷）和db/db（功能性瘦素受体缺陷）小鼠中形成的血栓是不稳定的并且经常栓塞。瘦素的给药稳定了ob/ob小鼠而非db/db小鼠形成的血栓，促进了ob/ob小鼠而非db/db小鼠的血小板聚集。这项研究的主要假设是瘦素与血小板上的受体结合，引起血小板信号传导和功能的生化变化，这是血栓稳定所必需的。在目的1中，骨髓移植研究和瘦素和瘦素抑制剂（例如，中和抗体）输注研究，以确定血栓中稳定性瘦素的来源、靶点和作用动力学，并检验瘦素减少将导致野生型小鼠中不稳定血栓形成的假设。瘦素促进血栓稳定性和增强血小板活化的机制将在目的2中研究。将检查最佳血小板需要瘦素的可能性：血小板和/或血小板血管壁相互作用，并确定瘦素和瘦素抑制剂对小鼠血小板聚集、分泌和信号传导的影响。初步研究表明，瘦素增强了来自某些供体的人血小板的聚集，而不是来自其他供体的人血小板的聚集。在目标3中，非应答性血小板中缺陷的性质（例如，瘦素受体的异常）。将测试瘦素抑制剂对响应性和非响应性血小板聚集以及对稳定“血栓”形成的影响。这些研究将提供新的见解，意想不到的作用，瘦素在血小板功能，血栓的形成和稳定性。