IFN-gamma, smooth muscle cells and graft arteriosclerosis

IFN-γ、平滑肌细胞与移植物动脉硬化

基本信息

批准号：
7675366
负责人：
George Tellides
金额：
$ 49.05万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7675366
关键词：
70-kDa Ribosomal Protein S6 Kinases 9-deoxy-delta-9-prostaglandin D2 Adenovirus Vector Affect Antigens Apoptosis Apoptotic Arteries Arteriosclerosis Biology Blood Vessels Blood flow Cell Death Cell Proliferation Cell Survival Cell model Cells Cessation of life Chronic Clinical Collaborations Complex Coronary Coronary artery Delayed Hypersensitivity Doctor of Medicine Doctor of Philosophy Double-Stranded RNA Endothelial Cells Failure Functional disorder Growth Factor Heart Transplantation Human Image Immune Immune response Immunodeficient Mouse In Vitro Infection Inflammation Inflammatory Interferon Activation Interferon Type II Interferons Jordan Leukocytes Ligands Mediating Methods Microarray Analysis Mitochondria Modeling Modification Molecular Mus Natural Immunity Nitric Oxide Noxae Nucleic Acids Nucleotides Outcome Study PPAR gamma Pathogenesis Pathology Pathway interactions Peroxisome Proliferator-Activated Receptors Process Production Proteins Research Personnel Role STAT protein Signal Pathway Signal Transduction Signaling Molecule Smooth Muscle Myocytes Staurosporine Stimulation of Cell Proliferation Stimulus T-Lymphocyte TNFSF10 gene TP53 gene Testing Thinking Tissues Transcript Translations Transplantation Up-Regulation Vascular remodeling XAF1 gene cytokine heart allograft human FRAP1 protein human HSXIAPAF1 protein in vivo inhibitor/antagonist interest mTOR Inhibitor novel novel therapeutics prevent programs receptor research study size synthetic nucleotide therapeutic target trafficking vascular smooth muscle cell proliferation

项目摘要

Chronic rejection, the major limitation of cardiac transplantation, is characterized by pathological remodeling and dysfunction of coronary arteries, termed graft arteriosclerosis (GA). The pathogenesis of GA is poorly understood, but is likely immune-mediated and may result from chronic delayed-type hypersensitivity responses by recipient T cells to donor vascular antigens through the secretion of cytokines, such as interferon-gamma (IFN-gamma). Paradoxically, IFN-gamma is generally thought to have an antiproliferative effect on vascular smooth muscle cells (VSMCs) and was considered to function as a proarteriosclerotic agent solely because of its immunomodulatory effects on endothelial cells and infiltrating leukocytes. However, we have found that IFN-gamma elicits arteriosclerosis in the absence of leukocytes. Our prior observations and current preliminary studies have led us to hypothesize that IFN-gamma induces VSMC proliferation that depends on a mTOR/p70S6K pathway, sensitizes VSMCs to apoptosis through upregulation of XAF1 and Noxa, and primes VSMCs for innate immune responses to fragmented nucleic acids by induction of RIG-I and MDA5. These disparate effects of IFN-gamma on VSMC survival and inflammation interact and cause intimal expansion, outward vascular remodeling, and vasodysfunction of conduit coronary arteries which ultimately determine lumen size and blood flow. We further hypothesize that these direct actions of IFN-gamma on VSMCs will be inhibited by peroxisome proliferator-activated receptor (PPAR)gamma ligands. To test our hypotheses with the experiments planned in this project, we have formed productive collaborations with other investigators of the program application and together we have developed novel models of GA in which human coronary arteries are interposed in severely immunodeficient mouse hosts that produce human IFN-gamma by adenoviral vector infection. Our methods are supplemented by mouse artery transplantation models and by cellular and molecular studies of human VSMCs. We will use these approaches to elucidate the effects of IFN-gamma on arterial tissue in vivo and in vitro. The outcomes of these studies will provide considerable new information about the role of IFN-gamma in GA, may identify novel therapeutic targets to treat and image GA, and investigate mechanisms of inhibiting GA by existing pharmacological agents.

慢性排斥反应是心脏移植的主要限制，其特点是病理重塑冠状动脉功能障碍，称为移植物动脉硬化（GA）。 GA的发病机制尚不清楚了解，但可能是免疫介导的，并且可能是由慢性迟发型超敏反应引起的受体 T 细胞通过分泌细胞因子对供体血管抗原做出反应，例如干扰素-γ（IFN-γ）。矛盾的是，IFN-γ 通常被认为对血管平滑肌细胞 (VSMC) 具有抗增殖作用，并且被认为具有促动脉硬化剂的作用，仅仅是因为其对内皮细胞和浸润白细胞的免疫调节作用。然而，我们发现在没有白细胞的情况下，IFN-γ会引起动脉硬化。我们之前的观察和目前的初步观察研究使我们推测 IFN-gamma 诱导 VSMC 增殖依赖于 mTOR/p70S6K 途径，通过上调 XAF1 和 Noxa 使 VSMC 对细胞凋亡敏感，并为 VSMC 做好准备通过诱导 RIG-I 和 MDA5 对片段化核酸产生先天免疫反应。这些不同的 IFN-γ 对 VSMC 存活的影响和炎症相互作用并导致内膜扩张、血管向外冠状动脉的重塑和血管功能障碍最终决定管腔大小和血流（量。我们进一步假设 IFN-γ 对 VSMC 的这些直接作用将被抑制过氧化物酶体增殖物激活受体 (PPAR) γ 配体。用实验来检验我们的假设在这个项目的计划中，我们与该项目的其他研究人员建立了富有成效的合作我们共同开发了新的 GA 模型，其中人类冠状动脉插入严重免疫缺陷的小鼠宿主中，通过腺病毒载体产生人干扰素-γ 感染。我们的方法得到小鼠动脉移植模型和细胞和人类 VSMC 的分子研究。我们将使用这些方法来阐明 IFN-gamma 对体内和体外的动脉组织。这些研究的结果将提供大量新信息关于 IFN-gamma 在 GA 中的作用，可能会确定治疗 GA 和成像的新治疗靶点，并进行研究现有药物抑制 GA 的机制。