权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
8117190
负责人：
George Tellides
金额：
$ 53.1万
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/8117190
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 Tissues Transcript Translations Transplantation Up-Regulation Vascular remodeling XAF1 gene cytokine heart allograft human FRAP1 protein in vivo inhibitor/antagonist interest mTOR Inhibitor new therapeutic target novel prevent programs receptor research study synthetic nucleotide 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因素，其特征是病理性重构和冠状动脉功能障碍，称为移植物动脉硬化（GA）。GA的发病机制不明确，可以理解，但可能是免疫介导的，可能由慢性迟发型超敏反应引起受体T细胞通过分泌细胞因子对供体血管抗原的应答，例如干扰素-γ（IFN-γ）。有趣的是，IFN-γ通常被认为对血管平滑肌细胞（VSMC）具有抗增殖作用，并且被认为仅作为促动脉炎剂起作用，因为其对内皮细胞和浸润性白细胞的免疫调节作用。然而，我们发现， IFN-γ在缺乏白细胞的情况下诱发动脉硬化。我们先前的观察和目前的初步研究使我们假设IFN-γ诱导VSMC增殖依赖于mTOR/p70 S6 K 途径，通过上调XAF 1和Noxa使VSMCs对凋亡敏感，并使VSMCs 通过诱导RIG-I和MDA 5对片段化核酸的先天免疫应答。这些不同 IFN-γ对VSMC存活和炎症的影响相互作用，导致内膜扩张，向外血管扩张，最终决定管腔大小的导管冠状动脉的重塑和血管功能障碍，血流我们进一步假设IFN-γ对VSMCs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。为了验证我们的假设计划在这个项目中，我们已经形成了富有成效的合作与其他研究人员的计划应用，我们一起开发了新的遗传算法模型，其中人类冠状动脉是通过腺病毒载体插入严重免疫缺陷小鼠宿主中产生人IFN-γ 感染我们的方法是补充小鼠动脉移植模型和细胞和人血管平滑肌细胞的分子研究。我们将使用这些方法来阐明IFN-γ对动脉组织在体内和体外。这些研究的结果将提供相当多的新信息关于IFN-γ在GA中的作用，可以确定新的治疗靶点来治疗和成像GA，并研究通过现有的药理学试剂抑制GA的机制。