Translation Studie of the Planet Specific Receptor Trem Like Transcript (TLT)

项目摘要 根据世界卫生组织，心血管疾病（CVD）是负责 占全球死亡人数的31%，是全球最大的死亡原因。这些数字是 在美国，超过60万人死于心血管疾病。CVD是一种炎症 血栓形成和血小板介导的炎症反应， 和CVD的血栓形成方面。我们的实验室研究了表达在细胞中的触发受体， 髓样细胞或（TLT-1），其储存在血小板的血小板颗粒中，并且都表达为 血小板活化后释放。TLT-1结合纤维蛋白原。而TLT-1 在心血管疾病、脓毒症和急性肺损伤中发挥作用， 与纤维蛋白原的关系知之甚少。我们假设TLT-1与纤维蛋白原的相互作用 是免疫系统征用止血系统的主要途径， 免疫功能在本申请中，我们提出机械地定义这种相互作用， 证明作为治疗靶点是有用的。我们提出以下三个目标： 使用双抗体夹心法测定纤维蛋白原与TLT-1和TLT IIb-2结合的相对贡献 缺陷型（treml 1-/-/itga 2b-/-）小鼠; Aim II -阐明TLT-1信号通路; Aim III - 评估TLT-1促血管生成剂对CVD和肥胖进展的影响。在 完成这些目标后，我们将确定TLT-1对血小板与血小板相互作用的贡献。 纤维蛋白原，并有可能作为治疗靶点。

Project Summary According to the World Health Organization, Cardiovascular disease (CVD) is responsible for 31% of deaths worldwide making it the largest global cause of mortality. These numbers are reflected in the United states where over 600,000 people died of CVD. CVD is an inflammatory disease that often leads to mortality by thrombosis and platelets mediate both the inflammatory and thrombotic aspects of CVD. Our laboratory studies the Triggering receptor expressed in myeloid cells or (TLT-1) that is stored in the granules of the platelets and is both expressed to the platelet surface and released after platelet activation. TLT-1 binds fibrinogen. While TLT-1 has demonstrated roles in Cardiovascular disease, sepsis, and acute lung injury, its interaction with fibrinogen is poorly understood. We hypothesize that TLT-1’s interaction with fibrinogen is a major pathway by which the immune system commandeers the hemostatic system for immune function. In this application we propose to mechanistically define this interaction and demonstrate is usefulness as a therapeutic target. We propose the following three aims: Aim I – Determine the relative contribution of fibrinogen binding to TLT-1 and IIb2 using double deficient (treml1-/-/itga2b-/-) mice; Aim II - Elucidate TLT-1 signaling pathways; Aim III – Evaluate the effect of TLT-1 prophylactics on the progression of CVD and obesity. At the completion of these aims we will have defined TLT-1’s contribution to platelet interaction with fibrinogen and is potential as a therapeutic target.