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.

慢性排斥是心脏移植的主要局限性，其特征是病理重塑冠状动脉动脉功能障碍，称为移植动脉硬化（GA）。 GA的发病机理很差理解，但可能是免疫介导的，可能是由于慢性延迟型超敏反应而引起的受体T细胞对供体血管抗原的反应通过细胞因子的分泌，例如干扰素 - 伽马（IFN-gamma）。自相矛盾的是，通常认为IFN-gamma对血管平滑肌细胞（VSMC）具有抗增殖作用，被认为是proarteriosclerotic剂的作用，仅仅是因为它对内皮细胞和浸润白细胞的免疫调节作用。但是，我们发现 IFN-gamma在缺乏白细胞的情况下引起动脉硬化。我们先前的观察和当前的初步研究使我们假设IFN-gamma诱导了取决于mTOR/p70s6k的VSMC增殖途径，通过上调xaf1和noxa，使VSMC对凋亡敏感，而Primes vsmcs则对通过诱导RIG-I和MDA5诱导对碎片核酸的先天免疫反应。这些不同 IFN-GAMMA对VSMC存活和炎症相互作用的影响并引起内膜膨胀，外部血管导管冠状动脉的重塑和血管函数，最终决定管腔尺寸和血流（量。我们进一步假设，IFN-GAMMA对VSMC的这些直接行动将受到过氧化物酶体增殖物激活受体（PPAR）伽马配体。通过实验检验我们的假设计划在这个项目中，我们与该计划的其他调查员建立了富有成效的合作应用，我们共同开发了GA的新型模型，其中人类冠状动脉是在严重免疫缺陷的小鼠宿主中插入了腺病毒载体产生人类IFN-gamma的宿主感染。我们的方法是由小鼠动脉移植模型以及细胞和人VSMC的分子研究。我们将使用这些方法来阐明IFN-Gamma对动脉组织体内和体外。这些研究的结果将提供大量的新信息关于IFN-GAMMA在GA中的作用，可以鉴定出新的治疗靶标，以治疗和图像GA，并研究现有药理剂抑制GA的机制。