STRESS SIGNALING PATHWAYS LINKING ENDOTHELIAL INJURY TO GRAFT ARTERIOSCLEROSIS

将内皮损伤与移植物动脉硬化联系起来的应激信号通路

• 批准号: 8441476
• 负责人: WANG MIN
• 金额: $ 39.6万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8441476
• 关键词: Acute; Affect; Alloantigen; Allogenic; Allografting; Antioxidants; Arteries; Arteriosclerosis; Automobile Driving; Biological Availability; Blood Vessels; Cell Adhesion Molecules; Cell physiology; Chronic; Clinical; Couples; Cytoplasm; Cytosol; Data; Delayed Hypersensitivity; Endothelial Cells; Endothelium; Exhibits; Failure; Functional disorder; Gene-Modified; Generations; Heart Transplantation; Heart failure; Human; Hydrogen Peroxide; Hyperplasia; Hypoxia; Immune system; In Vitro; Incidence; Inflammatory Response; Injury; Intercellular adhesion molecule 1; Interferon Type II; Interferons; Interleukin-1; Interleukin-2; Interleukin-6; Intracellular Signaling Proteins; Ischemia; Knock-out; Knockout Mice; Link; Mediating; Mediator of activation protein; Mitochondria; Modeling; Mus; NADPH Oxidase; Oxidases; Oxidative Stress; Pathogenesis; Patients; Production; Proteins; Reactive Oxygen Species; Reperfusion Therapy; Respiration; Role; Signal Pathway; Signal Transduction; Stenosis; Stress; System; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Thioredoxin-2; Transgenic Mice; Vascular Cell Adhesion Molecule-1; Vascular Diseases; allograft rejection; base; biological adaptation to stress; heart allograft; immunogenicity; in vivo; injured; isoimmunity; prevent; protective effect; response; success; vascular smooth muscle cell proliferation

DESCRIPTION (provided by applicant): The overall hypothesis of this application is that graft arteriosclerosis (GA), the major cause of late cardiac allograft failure, results from a chronic hot T cell response to allogeneic graft endothelial cells (ECs) that takes the form of delayed-type hypersensitivity DTH within the vessel wall, locally generating IFN-g which is responsible for driving vascular smooth muscle cell (VSMC) proliferation and intimal hyperplasia. The clinical correlations and evidence from other experimental systems have suggested that non-immune factors, especially peri-operative stress-induced alterations in the graft, are important contributors to GA pathogenesis. It is proposed and demonstrated experimentally that signals in the graft, primarily from ECs, generated as a result of peri-operative stress can produce mediators that influence T cell activation and differentiation. However, how the peri-operative stresses such as hypoxia couple intracellular signaling pathway to alter ECs alloimmunity and GA is not understood, and is the subject of this project. We have identified two major intracellular signaling proteins- cytosolic ASK1-interacting protein-1 (AIP1) and mitochondrial thioredoxin-2 (Trx2) in ECs that protect ECs from oxidative stress-induced injuries. Specifically, AIP1 in the cytoplasm via its inhibitory effect on the NADPH oxidase (Nox) while Trx2 in mitochondria via its anti-oxidant activity, prevent ischemia-reperfusion-elicited ROS and oxidative stress-induced inflammatory responses. In this proposal, we hypothesize that the responses to non-immune peri-operative injuries of graft endothelial cells (EC) are modulated by Trx2 in the mitochondria and AIP1 in the cytosol, altering the EC in a manner that affects T cell- mediated alloimmunity and GA. We propose to explore this hypothesis in the following specific aims: 1) Characterize AIP1-regulated cytosolic signaling pathways that mediate peri-operative stress-induced responses that alter EC immunogenicity and GA progression. 2) Characterize Trx2-regulated mitochondrial signaling pathways that mediate peri-operative stress-induced responses that alter EC immunogenicity and GA progression. If successful, this study will provide therapeutic strategies by modulating these two molecules in ECs to reduce GA incidence or delay GA progression.

描述（申请人提供）：本申请的总体假设是移植物动脉硬化（GA），晚期心脏同种异体移植物衰竭的主要原因，是由对同种异体移植物内皮细胞（EC）的慢性热T细胞应答引起的，其在血管壁内采取迟发型超敏反应DTH的形式，局部产生IFN-g，其负责驱动血管平滑肌细胞（VSMC）增殖和内膜增生。来自其他实验系统的临床相关性和证据表明，非免疫因素，特别是围手术期应激诱导的移植物改变，是GA发病机制的重要贡献者。它提出并证明实验中的移植物，主要是从内皮细胞，作为围手术期压力的结果产生的信号可以产生介质，影响T细胞的活化和分化。然而，围手术期应激如缺氧如何偶联细胞内信号通路来改变EC的同种免疫和GA尚不清楚，这是本项目的主题。我们已经确定了两个主要的细胞内信号蛋白-细胞溶质ASK 1相互作用蛋白-1（AIP 1）和线粒体硫氧还蛋白-2（Trx 2）在内皮细胞中保护内皮细胞免受氧化应激诱导的损伤。具体而言，细胞质中的AIP 1通过其对NADPH氧化酶（Nox）的抑制作用，而线粒体中的Trx 2通过其抗氧化活性，防止缺血-再灌注引起的ROS和氧化应激诱导的炎症反应。在该提议中，我们假设对移植物内皮细胞（EC）的非免疫围手术期损伤的反应由线粒体中的Trx 2和胞质溶胶中的AIP 1调节，以影响T细胞介导的同种异体免疫和GA的方式改变EC。我们建议在以下具体目标中探索这一假设：1）表征AIP 1调节的胞质信号传导途径，其介导围手术期应激诱导的反应，改变EC免疫原性和GA进展。2)表征Trx 2调节的线粒体信号通路，其介导围手术期应激诱导的反应，从而改变EC免疫原性和GA进展。如果成功，本研究将通过调节EC中的这两种分子来提供治疗策略，以降低GA发生率或延迟GA进展。