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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：迄今为止，所有已知的血小板和止血活化剂都是可溶的，细胞基质分子。 Kahn Lab证明了Podoplanin（PDPN），跨膜蛋白和血小板表面上的CLEC-2受体之间的相互作用可预防一生的血液淋巴混合。该途径需要CLEC2的血小板激活。来自Kahn Lab的研究揭示了该表型是在淋巴连接处的血小板介导的止血形式的一种新形式，该连接与CLEC2与淋巴内皮PDPN相互作用所刺激。 Bergmeier实验室最近与Kahn Lab合作，证明在肺和皮肤血管炎症期间止血还需要血小板CLEC2信号传导。拟议的研究将解决PDPN-CLEC2血小板激活的这些新的生物学作用，并研究血小板中CLEC2信号介导这种非典型止血反应的机制。 AIM 1将研究PDPN-CLEC2信号传导在预防肺和炎症性出血中的作用，这两个最近确定了该血小板激活途径的功能。 AIM 2将测试该途径是否参与血小板对血管壁损伤的反应，确定途径在炎症过程中阻止出血的机制，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激活途径，该途径在以前与血小板激活无关的止血作用与人类疾病高度相关。