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

基本信息

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
项目类别：
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

项目摘要

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.

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)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，非免疫因子，尤其是围手术性应力诱导的移植物变化，是GA发病机理的重要促进者。在实验上提出并证明，移植物中的信号主要来自EC，这是由于围手术应力而产生的，可以产生影响T细胞激活和分化的介体。然而，尚不了解围手术应力（例如缺氧对改变ECS同种免疫性和GA）的细胞内信号传导途径，这是该项目的主题。我们已经在EC中鉴定了两个主要的细胞内信号蛋白 - 胞质ASK1相互作用蛋白-1（AIP1）和线粒体硫氧还蛋白-2（TRX2），以保护ECS免受氧化应激诱导的损伤。具体而言，AIP1通过其抑制性对NADPH氧化酶（NOX）的抑制作用，而TRX2通过其抗氧化剂活性在线粒体中，预防缺血再灌注液的ROS和氧化应激诱导的炎症反应。在该提案中，我们假设对移植物内皮细胞（EC）的非免疫围手术损伤的反应受到线粒体中TRX2的调节和细胞溶胶中的AIP1，以影响T T细胞介导的全肌免疫和GA的方式改变EC。我们建议在以下特定目的中探索这一假设：1）表征AIP1调节的胞质信号传导途径，这些胞质信号传导途径介导了围手术量的应激诱导的反应，从而改变了EC免疫原性和GA的进展。 2）表征TRX2调节的线粒体信号传导途径，这些信号通路介导了围手术期应激诱导的反应，从而改变了EC免疫原性和GA的进展。如果成功，这项研究将通过调节EC中的这两个分子来减少GA发生率或延迟GA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的患者的生命，但其成功受到拒绝的形式，称为移植动脉硬化（ga），涉及逐渐缩小提供移植物的血管，值得通过可逆性应力来。该应用集中在两个关键分子AIP1和TRX2上，这些分子抑制了抑制可行应力。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发生率或延迟GA进展来提供治疗策略。