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激活剂都是可溶性细胞基质分子。 Kahn 实验室已经证明，平足蛋白 (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阻止整个生命过程中的血液与淋巴管的混合。该途径需要 CLEC2 激活血小板。 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一种新型止血，这种止血是由 CLEC2 与淋巴管内皮 PDPN 相互作用刺激的。 Bergmeier 实验室最近与 Kahn 实验室合作证明，血小板 CLEC2 信号传导对于肺部和皮肤血管炎症期间的止血也是必需的。拟议的研究将解决 PDPN-CLEC2 血小板激活的这些新生物学作用，并研究血小板中 CLEC2 信号传导介导此类非典型止血反应的机制。目标 1 将研究 PDPN-CLEC2 信号传导在预防肺出血和炎性出血中的作用，这是最近发现的血小板激活途径的两个功能。目标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，并确定血小板通过淋巴静脉止血保护淋巴网络的机制。这些研究将定义最近发现的血小板激活途径，该途径发挥以前与血小板激活无关的止血作用，而血小板激活与人类疾病高度相关。