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。该赠款将采用肥胖的鼠模型来描述潜在的机制。初步研究表明，响应动脉损伤（FECI3），在OB/OB（缺乏瘦素）和DB/DB（功能性瘦素受体缺陷型）小鼠中形成的血栓是不稳定的，并且经常栓塞。瘦素的给药稳定在OB/OB中形成的血栓，而不是在DB/DB小鼠中形成，并促进了来自OB/OB的血小板的聚集，但不是DB/DB小鼠。该赠款的主要假设是瘦素在血小板上与其受体结合，从而导致血小板稳定性所必需的血小板信号传导和功能的生化变化。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，以确定稳定瘦素在血栓中稳定瘦素的作用的起源，靶和动力学，并测试在瘦素中降低的假设会导致无效的thrombi thrombi的假设。瘦素促进血栓稳定性并增强血小板激活的机制将在AIM 2中进行研究。最佳血小板所需的瘦素可能需要检查血小板和/或血小板血管壁相互作用，并且将检查瘦素和瘦素抑制剂对聚集，分泌，分泌和信号的作用。初步研究表明，瘦素增强了一些捐赠者的人血小板的聚集，但不是其他捐助者的聚集。在AIM 3中，将检查无反应性血小板中缺陷的性质（例如，瘦素受体异常）。瘦素抑制剂对响应式和无反应性血小板的聚集以及稳定“血栓”的形成的影响。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外作用提供新的见解。