Spatial regulation of platelet activation by Podoplanin-Clec2 signaling

Podoplanin-Clec2 信号传导对血小板活化的空间调节

• 批准号: 8761615
• 负责人: Wolfgang Bergmeier
• 金额: $ 32.7万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8761615
• 关键词: Address; Adult; Affect; Air; Alveolar Cell Type I; Alveolus; Arterial Injury; Biological; Blood; Blood Platelets; Blood Vessels; Brain; C Type Lectin Receptors; C-Type Lectins; Cell Wall; Cells; Characteristics; Chemicals; Coagulation Process; Congestive Heart Failure; Coronary artery; Cutaneous; Development; Disease; Environment; Fibrin; Gases; Generations; Genetic; Glycoproteins; Hematopoietic; Hemorrhage; Hemostatic Agents; Hemostatic function; Human; Inflammation; Inflammatory; Inflammatory Response; Injury; Integral Membrane Protein; Lead; Life; Lung; Lymphatic; Lymphatic Endothelial Cells; Mediating; Membrane Proteins; Modeling; Mus; Neuraxis; Organ; Pathway interactions; Patients; Pericytes; Phenotype; Platelet Activation; Proteins; Publishing; Regulation; Role; Secure; Signal Pathway; Signal Transduction; Site; Skin; Source; Stress; Surface; Testing; Thromboplastin; Thrombosis; Thrombus; Tissues; Translations; Venous; base; cell type; human disease; in vivo; lung injury; macrophage; novel; podocyte; podoplanin; prevent; public health relevance; receptor; response; response to injury; selective expression; vascular inflammation

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.

描述（由申请方提供）：迄今为止，所有已知的血小板和止血激活剂均为可溶性细胞基质分子。Kahn实验室已经证明，podoplanin（PDPN），一种跨膜蛋白，与血小板表面的CLEC-2受体之间的相互作用可以防止血液-淋巴混合。该途径需要CLEC 2激活血小板。来自Kahn实验室的研究揭示了这种表型的基础是淋巴-静脉交界处血小板介导的止血的新形式，其由CLEC 2与淋巴内皮PDPN的相互作用刺激。Bergmeier实验室最近与Kahn实验室合作，证明血小板CLEC 2信号传导也是肺和皮肤血管炎症期间止血所必需的。拟议的研究将解决PDPN-CLEC 2血小板活化的这些新的生物学作用，并研究血小板中CLEC 2信号传导介导这种非典型止血反应的机制。目的1将研究PDPN-CLEC 2信号传导在预防肺出血和炎性出血中的作用，这是该血小板活化途径的两个最近确定的功能。目的2将测试该通路是否参与血小板对血管壁损伤的反应，确定该通路在炎症期间防止出血的机制，并确定通过淋巴静脉止血保护淋巴网络的血小板机制。这些研究将定义最近发现的血小板活化途径，该途径发挥与人类疾病高度相关的先前与血小板活化无关的止血作用。