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

项目摘要 根据世界卫生组织的说法，心血管疾病(CVD)是导致 占全球死亡人数的31%，成为全球最大的死亡原因。这些数字是 反映在美国，有60多万人死于心血管疾病。心血管疾病是一种炎症性疾病 通常通过血栓形成导致死亡的疾病和血小板都是炎症的媒介 以及脑血管疾病的血栓方面。我们的实验室研究了细胞内表达的触发受体 髓系细胞或(TLT-1)，储存在血小板的颗粒中，两者都表达于 活化后的血小板表面和释放。TLT-1与纤维蛋白原结合。而TLT-1 已经证明在心血管疾病、脓毒症和急性肺损伤中的作用，其相互作用 与纤维蛋白原有关的情况知之甚少。我们推测TLT-1‘S与纤维蛋白原相互作用 是免疫系统征用止血系统的主要途径 免疫功能。在本应用程序中，我们建议机械地定义这种相互作用 作为治疗靶点，演示是有用的。我们提出以下三个目标：目标I- 用双抗体夹心法测定纤维蛋白原结合对TLT-1和IIb2的相对贡献 目的II-阐明TLT-1信号通路；目的III- 评价TLT-1预防用药对心血管疾病进展和肥胖的影响。在 完成这些目标后，我们将明确TLT-1‘S对血小板相互作用的贡献 纤维蛋白原，是潜在的治疗靶点。

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.