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: 8292774
• 负责人: WANG MIN
• 金额: $ 41.47万
• 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/8292774
• 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. PUBLIC HEALTH RELEVANCE: Heart transplantation can saves lives of patients with severe heart failure but its success is limited by a form of late rejection, called graft arteriosclerosis (GA), that involves progressive narrowing of the blood vessels supplying the graft and is worthend by peroperative stresses. This application focuses on two critical molecules AIP1 and Trx2 that suppresses the peroperative stresses. If successful, this study will provide therapeutic strategies by modulating these two molecules in grafts 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)，移植物动脉硬化(GA)是晚期心脏移植失败的主要原因，是由于T细胞对同种异体移植内皮细胞(ECs)的慢性热反应所致，这种反应在血管壁内以迟发性超敏DTH的形式出现，局部产生干扰素-g，负责驱动血管平滑肌细胞(VSMC)的增殖和内膜增生。临床相关性和来自其他实验系统的证据表明，非免疫因素，特别是围手术期应激诱导的移植物改变，是GA发病的重要因素。有人提出并实验证明，移植物中的信号，主要来自内皮细胞，是围手术期应激产生的结果，可以产生影响T细胞激活和分化的介质。然而，围术期应激，如低氧，如何结合细胞内信号通路改变内皮细胞同种免疫和GA尚不清楚，这是本项目的主题。我们已经在内皮细胞中发现了两种主要的细胞内信号蛋白--胞浆ASK1相互作用蛋白-1(AIP1)和线粒体硫氧还蛋白-2(Trx2)，它们可以保护内皮细胞免受氧化应激诱导的损伤。具体地说，AIP1在细胞质中通过其对NADPH氧化酶(Nox)的抑制作用，而Trx2在线粒体中通过其抗氧化活性，防止缺血再灌注引起的ROS和氧化应激诱导的炎症反应。在这个提议中，我们假设移植物内皮细胞(EC)对围手术期非免疫性损伤的反应是由线粒体中的Trx2和胞浆中的AIP1调节的，从而以一种影响T细胞介导的同种免疫和GA的方式改变EC。我们建议在以下特定目标下探索这一假说：1)表征AIP1调节的胞浆信号通路，该通路介导围手术期应激诱导的反应，从而改变EC的免疫原性和GA进展。2)表征Trx2调控的线粒体信号通路，这些信号通路介导围手术期应激诱导的反应，从而改变EC的免疫原性和GA进展。如果成功，这项研究将通过调节内皮细胞中的这两个分子来减少GA的发生率或延缓GA的进展，从而提供治疗策略。 公共卫生相关性：心脏移植可以挽救严重心力衰竭患者的生命，但其成功受到一种称为移植物动脉硬化的晚期排斥反应的限制。 (Ga)，这涉及到供血血管的进行性狭窄，值得通过围手术期的压力来解决。这一应用集中在抑制围手术期应激的两个关键分子AIP1和Trx2上。如果成功，这项研究将通过调节移植物中的这两个分子来减少GA的发生率或延缓GA的进展，从而提供治疗策略。