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The Annexin 2 Stress Response in Vascular Cells

血管细胞中的膜联蛋白 2 应激反应

基本信息

批准号：
7218204
负责人：
KATHERINE AMBERSON HAJJAR
金额：
$ 43.77万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-12-01 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7218204
关键词：
A Mouse ATP-Binding Cassette Transporters Acute Promyelocytic Leukemia Alteplase Animal Model Annexins Antibodies Antiphospholipid Syndrome Arterial Fatty Streak Arterial Injury Atherosclerosis Attenuated Binding Binding Proteins Blast Cell Blood Vessels CCL2 gene Calcium Cardiovascular Diseases Cell surface Cells Data Defect Developed Countries Developing Countries Disabled Persons Disease Endopeptidases Endoplasmic Reticulum Endothelial Cells Environment Event Family Family member Fibrin Fibrinolysis Generations Golgi Apparatus Growth Factor Health Heat Stress Disorders Hemorrhage Human In Vitro Incidence Injury Invasive Laboratories Mediating Medical Surveillance Molecular Pathway interactions Peptide Hydrolases Peptide Signal Sequences Phospholipids Phosphorylation Phosphotransferases Phylogenetic Analysis Physiological Plasmin Plasminogen Play Process Property Protein Overexpression Proteins Publishing Regulation Research Personnel Role S100 family protein p11 Signal Transduction Smooth Muscle Myocytes Stress Supporting Cell Surface System Tangier Disease Thrombin Thrombosis Trees Tyrosine Tyrosine Phosphorylation Vascular Endothelial Cell Work activator 1 protein base biological adaptation to stress cell injury cell motility cholesterol transporters cytokine extracellular in vivo macrophage member migration monocyte mouse model platelet-derived growth factor BB postnatal receptor receptor binding response response to injury restenosis

项目摘要

Atherosclerosis is a major cause of cardiovascular disease in developed countries. In this disorder, endothelial cells acquire procoagulant properties, while activated smooth muscle cells and macrophages accumulate in the arterial wall. The overall objective of this project will be to understand the regulation of the annexin 2 (A2)-based proteolytic cascade, initiated by plasmin, on the surface of vascular cells. A2 is a major profibrinolytic receptor expressed on endothelial cells, activated smooth muscle cells, and macrophages. A2 accelerates plasmin generation by several orders of magnitude, and plays a central role in directed vascular cell migration and matrix remodeling, through the activation of additional downstream proteases. Preliminary data suggest that translocation of A2 to the cell surface is a primary mechanism by which vascular cells (endothelial cells, smooth muscle cells, and macrophages) upregulate cell surface proteolytic activity. In this proposal, we will elucidate the molecular pathways that govern the transport of A2 to the cell surface in response to stress and/or injury to vascular cells. Previously, we demonstrated that A2 is exported from a cytoplasmic compartment to the cell surface through a non-classical, Golgi/endoplasmic reticulum-independent pathway initiated by brief heat stress. We showed that this regulated response requires the participation of the A2 binding protein, p11 (S100A10), which enables a src-like, kinase- mediated tyrosine-23 phosphorylation switch that initiates the translocation response. In the proposed studies, we will examine [1] the mechanism by which endothelial cells, smooth muscle cells, and macrophages translocate A2 to the cell surface in response to injury, [2] the role of the ATP binding cassette transporter A1 (ABCA1) in this process, [3] the specific role of the A2-binding protein, p11, in A2 translocation, and [4] the significance of A2 transport in the response to vascular injury in vivo. These studies will utilize combined approaches involving in vitro culture systems and genetically modified mouse models, including A2 and p11 -nulls created in our laboratory. We will continue to collaborate with investigators in Projects III and V to capitalize on their expertise in the study of the growth factor signalling and cholesterol transporter mechanisms.

动脉粥样硬化是发达国家心血管疾病的主要原因。在这种紊乱中，