Thrombus Formation Initiation and Propagation

血栓形成起始和传播

• 批准号: 7093636
• 负责人: BARBARA C FURIE
• 金额: $ 41.5万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-02 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7093636
• 关键词: arterioles; cell surface receptors; coagulation factor IX; coagulation factor XI; collagen; glycoproteins; laboratory mouse; lasers; ligands; nuclear magnetic resonance spectroscopy; phosphatidylserines; platelets; selectins; thromboplastin; thrombosis

DESCRIPTION (provided by applicant): The objectives of this proposal are to determine the role of platelet collagen receptors and of factor XI in thrombus formation in vivo. While the role of these components of the hemostatic system have been well studied in vitro and mutations in some of the participating proteins in humans hint at in vivo roles, the opportunity now exists, using a unique real time intravital microscopy technique, to delineate their importance in vivo. The time course and kinetics of laser induced thrombus formation in the arterioles of mice glycoprotein VI null mice, mice with low levels of glycoprotein VI and mice lacking the integrin alpha2 beta1 will be examined to determine the role of these collagen receptors in thrombus formation in this model. The activation state of the platelets accumulating in thrombi in the three mouse genotypes will be examined to probe the role of the two different collagen receptors in platelet signaling in response to collagen. Both mice lacking glycoprotein VI and mice lacking the alpha2 integrin chain appear to be protected in mouse models of thrombosis but in contrast to the bleeding phenotype present in deficiency of glycoprotein Ib, another initiator of platelet adhesion at sites of injury, mice lacking glycoprotein VI or the alpha2 integrin chain do not bleed. Thus these proteins may be useful targets for anti-thrombotic agents warranting a better understanding of their role in thrombus formation in vivo. A current model for blood coagulation is that the initiation occurs through exposure of tissue factor at sites of vascular injury resulting in the generation of small quantities of factor Xa and thrombin. The amount of thrombin generated through this pathway is limited by the inhibition of the factor Vlla-tissue factor complex by TFPI, in the presence of factor Xa. The initial thrombin among other functions formed activates factor XI which then maintains the thrombin flux through activation of factor IX. The time course and kinetics of laser induced thrombus formation in factor XI null mice will be examined to obtain a better understanding of the role of factor XI in vivo. The elucidation of the molecular architecture of blood coagulation complexes remains one of the major unresolved problems in the understanding of this process. To complement our in vivo studies of the role of factor XI in thrombus formation the structure of the complex formed between the factor XI apple domain(s)and the factor IX Gla domain will be determined.

描述（由申请人提供）：该提案的目标是确定血小板胶原受体和因子XI在体内血栓形成中的作用。尽管已经在体外进行了充分研究了止血系统的这些成分的作用，并且在人类中的某些参与蛋白中的突变暗示了体内的角色，但现在存在机会，使用独特的实时内部插入显微镜技术来描述其在体内的重要性。激光诱导的小鼠糖蛋白VI无效的小鼠的时间过程和动力学，糖蛋白VI无效的小鼠，低水平的糖蛋白VI和缺乏整联蛋白alpha2 beta1的小鼠将被检查以确定这些胶原受体在该模型中的作用。将检查三种小鼠基因型中血栓中积累的血小板的活化态，以探测两个不同的胶原受体在血小板信号传导中的作用，响应胶原蛋白。缺乏糖蛋白VI和缺乏α2整联蛋白链的小鼠在血栓形成的小鼠模型中都受到保护，但与糖蛋白IB缺乏的出血表型相反，糖蛋白IB的出现表型，糖蛋白IB的缺乏，这是受伤部位的另一个缺乏血小板粘附的启动剂，在受伤的部位，缺乏糖蛋白VI vi vi or the Alpha ble ble ble ble ble ble ble ble ble ble ble ble。因此，这些蛋白质可能是抗凝血药物的有用靶标，可以更好地了解其在体内血栓形成中的作用。当前的血液凝结模型是，起始是通过在血管损伤部位暴露于组织因子而发生的，从而导致少量因子Xa和凝血酶产生。在存在因子Xa的情况下，通过该途径产生的凝血酶量受TFPI对因子VLLA组织因子复合物的抑制限制。最初的凝血酶在其他功能中形成了因子XI，然后通过激活因子IX来维持凝血酶通量。将检查激光诱导因子XI null小鼠中的血栓形成的时间过程和动力学，以更好地了解XI因子在体内的作用。阐明血液凝结复合物的分子结构仍然是理解该过程的主要未解决问题之一。为了补充我们对因子XI在血栓形成中的作用的体内研究，将确定因子XI X Apple结构域和因子IX GLA结构域之间形成的复合物的结构。