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：
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
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/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

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.

描述（由申请人提供）：本申请的总体假设是，移植物动脉硬化（GA）是晚期同种异体心脏移植失败的主要原因，是由对同种异体移植物内皮细胞（EC）的慢性热T细胞反应引起的，其形式为血管壁内迟发型超敏反应的DTH，局部产生IFN-g，负责驱动血管平滑肌细胞（VSMC）增殖和内膜增生。临床相关性和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引起的移植物变化，是 GA 发病机制的重要贡献者。实验提出并证明，移植物中的信号（主要来自内皮细胞）因围手术期应激而产生，可以产生影响 T 细胞活化和分化的介质。然而，围手术期应激（例如缺氧）如何与细胞内信号通路结合以改变 EC 的同种免疫和 GA 尚不清楚，这也是本项目的主题。我们在 EC 中发现了两种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)，它们可以保护 EC 免受氧化应激引起的损伤。具体来说，细胞质中的 AIP1 通过其对 NADPH 氧化酶 (Nox) 的抑制作用，而线粒体中的 Trx2 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。在本提案中，我们假设移植物内皮细胞 (EC) 对围手术期非免疫损伤的反应是由线粒体中的 Trx2 和胞质溶胶中的 AIP1 调节的，从而以影响 T 细胞介导的同种免疫的方式改变 EC和遗传算法。我们建议在以下具体目标中探索这一假设：1）表征 AIP1 调节的胞质信号通路，这些信号通路介导围手术期应激诱导的反应，从而改变 EC 免疫原性和 GA 进展。 2) 表征 Trx2 调节的线粒体信号通路，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，这项研究将通过调节 EC 中的这两种分子来提供治疗策略，以降低 GA 发生率或延缓 GA 进展。