The Annexin 2 Stress Response in Vascular Cells

血管细胞中的膜联蛋白 2 应激反应

• 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
• 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

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。在这种混乱中， 内皮细胞获得促凝血特性，同时激活平滑肌细胞和巨噬细胞 积聚在动脉壁内。该项目的总体目标是了解 血管细胞表面由纤溶酶引发的基于膜联蛋白 2 (A2) 的蛋白水解级联反应。 A2 是一个 在内皮细胞、活化的平滑肌细胞和激活的平滑肌细胞上表达的主要纤溶原受体 巨噬细胞。 A2 可将纤溶酶的生成加速几个数量级，并发挥核心作用 在定向血管细胞迁移和基质重塑中，通过激活额外的下游 蛋白酶。初步数据表明，A2 易位至细胞表面是主要机制： 哪些血管细胞（内皮细胞、平滑肌细胞和巨噬细胞）上调细胞表面 蛋白水解活性。在本提案中，我们将阐明控制 A2 运输的分子途径 细胞表面响应血管细胞的压力和/或损伤。之前，我们证明了 A2 通过非经典的高尔基体/内质从细胞质室输出到细胞表面 由短暂的热应激启动的网状独立通路。我们证明了这种调节反应 需要 A2 结合蛋白 p11 (S100A10) 的参与，它能够实现类似 src 的激酶- 介导的 23 酪氨酸磷酸化开关启动易位反应。在提议的 研究中，我们将研究[1]内皮细胞、平滑肌细胞和 巨噬细胞响应损伤将 A2 易位至细胞表面，[2] ATP 结合盒的作用 转运蛋白 A1 (ABCA1) 在此过程中，[3] A2 结合蛋白 p11 在 A2 中的特定作用 易位，以及 [4] A2 转运在体内血管损伤反应中的意义。这些 研究将利用涉及体外培养系统和转基因小鼠的组合方法 模型，包括我们实验室创建的 A2 和 p11 -nulls。我们将继续与以下机构合作 项目 III 和 V 的研究人员利用他们在生长因子信号传导研究中的专业知识 和胆固醇转运机制。