IFN gamma in human GA

人 GA 中的 IFN γ

• 批准号: 7117154
• 负责人: George Tellides
• 金额: $ 19.39万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 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/7117154
• 关键词: SCID mouse; acute phase protein; animal tissue; arteriosclerosis; blood vessel transplantation; human tissue; interferon gamma; organ culture; platelet derived growth factor; transcription factor; transplant rejection; vascular smooth muscle

IFN-gamma in Human Graft Arteriosclerosis is the major limitation of cardiac transplantation and 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 (DTH) responses by recipient T cells to donor vascular antigens. Activated T cells induced DTH through secretion of cytokines, such as interferon-gamma (IFN-gamma). Paradoxically, IFN-gamma is generally thought to have an anti-proliferative effect on vascular smooth muscle cells (VSMCs) and considered to function as a pro-arteriosclerotic agent solely because of its immunomodulatory effects on vascular cells and infiltrating leukocytes. However, we have recently reported that IFN- gamma elicits arteriosclerosis in the absence of leukocytes. Our observations have led us to hypothesize that IFN-gamma acts directly on VSMCs to potential platelet-derived growth factor (PDGF)-BB induced mitogenesis through interactions involving growth factor receptors and STAT proteins. To test our hypothesis 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 by establishing methods to transplant human and pig coronary arteries to immunodeficient mouse hosts and by defining conditions for the long-term organ culture of human and pig coronary arteries. We will use these approaches to elucidate the effects of IFN- gamma on vascular tissues in vivo and in vitro. The aims of our application are: (1) to test the hypothesis that IFN-gamma growth stimulatory signals to VSMCs are mediated by STAT3 and are enhanced by PDGF-BB; (2) to test the hypothesis that IFN-gamma growth inhibitory signals to VSMCs are mediated by STAT1 and are diminished by PDGF-BB; (3) to test the hypothesis that IFN-gamma induced proliferation of VSMCs is independent of IFN-gamma effects on endothelial cells; and (4) to validate our model by confirming that the expression of certain IFN gamma-dependent gene products correlates with the presence and degree of GA in human cardiac allografts the outcomes of these studies will provider considerable new information about the role of IFN-gamma in GA. Our experimental work performed in conjunction with Cores B and C will provide a mechanistic extension to the studiers of Project 1. The reagents we characterize in conjunction with Cores D and E will be applied in imaging studies by Project 3. The comparisons between experimental and clinical specimens in conjunction with Project 3, Cores D and E will validate our models. Our findings may ultimately have diagnostic, prognostic, and therapeutic clinical utility.

移植物动脉硬化是心脏移植的主要限制，其特征是冠状动脉的病理性重塑和功能障碍，称为移植物动脉硬化（GA）。GA的发病机制尚不清楚，但可能是免疫介导的，可能是由受体T细胞对供体血管抗原的慢性延迟型超敏反应（DTH）引起的。活化的T细胞通过分泌细胞因子，如干扰素- γ (ifn - γ)诱导DTH。矛盾的是，ifn - γ通常被认为对血管平滑肌细胞（VSMCs）具有抗增殖作用，并被认为是一种促动脉硬化剂，仅仅是因为它对血管细胞和浸润性白细胞具有免疫调节作用。然而，我们最近报道了IFN- γ在缺乏白细胞的情况下引起动脉硬化。我们的观察结果使我们假设ifn - γ通过涉及生长因子受体和STAT蛋白的相互作用，直接作用于VSMCs到潜在的血小板衍生生长因子(PDGF)-BB诱导的有丝分裂发生。为了用本项目中计划的实验来验证我们的假设，我们与项目应用的其他研究人员建立了富有成效的合作关系，通过建立将人类和猪冠状动脉移植到免疫缺陷小鼠宿主的方法，以及通过确定人类和猪冠状动脉长期器官培养的条件，我们共同开发了新的GA模型。我们将使用这些方法来阐明IFN- γ对体内和体外血管组织的影响。本研究的目的是：(1)验证向VSMCs发送的ifn - γ生长刺激信号是由STAT3介导的，并被PDGF-BB增强；(2)验证ifn - γ对VSMCs的生长抑制信号由STAT1介导，PDGF-BB减弱的假设；(3)验证ifn - γ诱导VSMCs增殖与ifn - γ对内皮细胞的作用无关的假设；(4)通过证实某些IFN γ依赖基因产物的表达与人类同种异体心脏移植物中GA的存在和程度相关来验证我们的模型，这些研究的结果将提供有关IFN- γ在GA中的作用的大量新信息。我们与核心B和核心C一起进行的实验工作将为项目1的研究人员提供一个机制上的扩展。我们与核心D和E一起描述的试剂将在项目3的成像研究中应用。结合项目3、核心D和E的实验和临床标本的比较将验证我们的模型。我们的发现可能最终具有诊断、预后和治疗的临床价值。