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。这笔赠款将采用小鼠肥胖模型来描绘潜在的机制。初步研究表明，ob/ob（瘦素缺乏）和 db/db（功能性瘦素受体缺乏）小鼠响应动脉损伤 (FeCI3) 形成的血栓不稳定且经常发生栓塞。施用瘦素可以稳定ob/ob小鼠中形成的血栓，但不能稳定db/db小鼠中形成的血栓，并促进ob/ob小鼠中血小板的聚集，但不能促进db/db小鼠中的血小板聚集。这项资助的主要假设是瘦素与其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，这是血栓稳定性所必需的。在目标 1 中，将进行骨髓移植研究以及瘦素和瘦素抑制剂（例如中和抗体）输注研究，以确定血栓中稳定瘦素的起源、靶点和动力学，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。目标 2 将研究瘦素促进血栓稳定性和增强血小板活化的机制。将检查瘦素对于最佳血小板所需的可能性：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，瘦素可以增强某些供体的人类血小板的聚集，但不能增强其他供体的血小板的聚集。在目标 3 中，将检查无反应血小板缺陷的性质（例如瘦素受体异常）。将测试瘦素抑制剂对反应性和非反应性血小板聚集以及稳定“血栓”形成的影响。这些研究将为瘦素在血小板功能以及血栓形成和稳定性中的意想不到的作用提供新的见解。