Spatial regulation of platelet activation by Podoplanin-Clec2 signaling

描述(申请人提供)：到目前为止，所有已知的血小板和止血激活剂都是可溶性和细胞基质分子。卡恩实验室已经证明，一种跨膜蛋白泊多普宁(PDPN)与血小板表面的CLEC-2受体之间的相互作用会在一生中阻止血液和淋巴的混合。这一途径需要CLEC2激活血小板。卡恩实验室的研究揭示了这种表型的基础是一种新型的血小板介导的淋巴-静脉连接处止血，这种止血是由CLEC2与淋巴管内皮细胞PDPN相互作用所刺激的。Bergmeier实验室最近与Kahn实验室合作，证明在肺和皮肤的血管炎症过程中，血小板CLEC2信号也是止血所必需的。建议的研究将探讨PDPN-CLEC2血小板激活的这些新的生物学作用，并探讨血小板中CLEC2信号介导这种非典型止血反应的机制。目的1研究PDPN-CLEC2信号在预防肺出血和炎性出血中的作用，这是最近发现的这一血小板活化途径的两个功能。目的2检测该通路是否参与了血小板对血管壁损伤的反应，确定该通路防止炎症时出血的机制，并确定通过淋巴-静脉止血保护淋巴网的血小板机制。这些研究将确定最近发现的一种血小板激活途径，该途径执行以前与血小板激活无关的止血作用，而这些作用与人类疾病高度相关。

DESCRIPTION (provided by applicant): To date, all of the known activators of platelets and hemostasis are soluble and cell matrix molecules. The Kahn lab has demonstrated that interactions between podoplanin (PDPN), a transmembrane protein, and CLEC-2 receptors on the surface of platelets prevent blood-lymphatic mixing throughout life. This pathway requires platelet activation by CLEC2. Studies from the Kahn lab reveal the basis for this phenotype to be a novel form of platelet-mediated hemostasis at the lympho-venous junction that is stimulated by CLEC2 interaction with lymphatic endothelial PDPN. The Bergmeier lab has recently collaborated with the Kahn lab to demonstrate that platelet CLEC2 signaling is also required for hemostasis during vascular inflammation in the lung and skin. The proposed studies will address these new biological roles of PDPN-CLEC2 platelet activation, and investigate the mechanism by which CLEC2 signaling in platelets mediates such non-canonical hemostatic responses. Aim 1 will investigate the role of PDPN-CLEC2 signaling in preventing pulmonary and inflammatory hemorrhage, two very recently identified functions of this platelet activation pathway. Aim 2 will test whether this pathway participates in platelet responses to vessel wall injury, determine the mechanism by which the pathway prevents hemorrhage during inflammation, and identify the platelet mechanisms that protect the lymphatic network through lympho- venous hemostasis. These studies will define a recently discovered platelet activation pathway that performs hemostatic roles not previously associated with platelet activation that are highly relevant for human disease.