Translation Studies 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），储存在血小板的α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 是免疫系统控制止血系统的主要途径 免疫功能。在本申请中，我们建议机械地定义这种相互作用 并证明其作为治疗靶点的有用性。我们提出以下三个目标： 目的I -确定纤维蛋白原与TLT-1和αIIbβ2结合的相对贡献 使用双缺陷（treml 1-/-/itga 2b-/-）小鼠;目的II -阐明TLT-1信号传导 目的III -评价TLT-1药物对CVD进展的影响 和肥胖。在完成这些目标时，我们将确定TLT-1对以下方面的贡献： 血小板与纤维蛋白原的相互作用，并有可能作为治疗靶点。在本补充中，我们 将研究TLT-1在维持血脑屏障完整性方面的作用

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 α-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 its usefulness as a therapeutic target. We propose the following three aims: Aim I – Determine the relative contribution of fibrinogen binding to TLT-1 and αIIbβ2 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. In this supplement we will look at the role of TLT-1 in maintaining the integrity of the blood-brain barrier