INFLAMMATORY MECHANISMS OF NEOINTIMAL HYPERPLASIA

新生内膜增生的炎症机制

• 批准号: 6536568
• 负责人: C KEITH OZAKI
• 金额: $ 12.34万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6536568
• 关键词: artery; blood vessel disorder; cytokine receptors; hyperplasia; inflammation; interleukin 10; laboratory mouse; tumor necrosis factor alpha; vascular endothelium

Cardiovascular disorders continue to lead national morbidity, mortality, and cost figures. Neointimal hyperplasia stands as the underlying pathophysiology of many of these disorders. Inflammation has been associated with neointimal hyperplasia and the related process of atherogenesis, although it remains uncertain whether arterial remodeling occurs by way of inflammatory dependent mechanisms, or whether the inflammation is a secondary event. The current proposal details a research and training program that combines didactic courses, quality interactions with established investigators, and a hypothesis driven mechanistic research plan. Additionally, it provides new training in cytokine biology, advanced immunohistochemistry methods and gene therapy approaches. The grant has been thoughtfully constructed to help the Principal Investigator reach his long-term career goal of independent investigatorship as an academic vascular surgeon and to simultaneously advance our understanding of the mechanisms of neointimal hyperplasia. The overall scientific hypothesis of this training program is that neointimal hyperplasia proceeds by way of inflammatory dependent mechanisms. In this project we will dissect the roles of the pro-inflammatory cytokine TNF-alpha, and the anti-inflammatory cytokine IL-10, in neointima formation. Preliminary studies in a murine model suggest absence of biologically active TNF-alpha results in ten-fold less neointima formation. The chronology and cellular mediators (leukocytes and smooth muscle cells) of this TNF-alpha effect are unknown, and will be defined in this study. Because TNF-alpha can signal through two distinct receptors, TNFRI (P55) and TNFRII (p75), we will ascertain (using a genetic approach) through which receptor is TNF-alpha signaling accomplished in the setting of arterial remodeling. We hypothesize that endogenous TNF- alpha chronically upregulates neointimal hyperplasia through enhanced artery wall inflammation by way of signaling through the p55 receptor. IL-10 is an anti-inflammatory cytokine that stands as a primary endogenous downregulator of TNF-alpha. Preliminary studies suggest that delivery of viral IL-10 by way of gene therapy approaches attenuates neointimal hyperplasia. Using genetic, pharmacologic, and gene therapy approaches we will determine if neointimal hyperplasia is modulated by IL-10 dependent mechanisms, and the cellular events by which this sequence proceeds. We hypothesize that Ill-10 downregulates neointimal hyperplasia. TNF-alpha and IL-10 mediated cellular processes serve as a potential site for therapeutically interrupting pathologic arterial remodeling.

心血管疾病继续在全国发病率、死亡率和成本数据中居于首位。新生内膜增生是许多此类疾病的潜在病理生理学基础。炎症与动脉内膜增生和动脉粥样硬化的相关过程有关，尽管目前尚不清楚动脉重构是通过炎症依赖机制发生的，还是炎症是继发性事件。目前的提案详细说明了一项研究和培训计划，该计划结合了教学课程、与现有研究人员的高质量互动，以及假设驱动的机械性研究计划。此外，它还提供细胞因子生物学、先进的免疫组织化学方法和基因治疗方法方面的新培训。这笔拨款是经过深思熟虑的，目的是帮助首席研究员实现他作为一名学术血管外科医生的独立研究的长期职业目标，同时促进我们对新生内膜增生机制的理解。该培训计划的总体科学假设是，新生内膜增生是通过炎症依赖机制进行的。在这个项目中，我们将剖析促炎细胞因子TNF-α和抗炎细胞因子IL-10在新生内膜形成中的作用。在小鼠模型中的初步研究表明，缺乏生物活性的肿瘤坏死因子-α会导致新生内膜形成减少十分之一。这种肿瘤坏死因子-α效应的时间顺序和细胞介质(白细胞和平滑肌细胞)是未知的，将在这项研究中定义。由于肿瘤坏死因子-α可以通过两种不同的受体，即TNFRI(P55)和TNFRII(P75)来传递信号，因此我们将(使用遗传学方法)确定在动脉重塑的背景下，是通过哪一种受体来传递信号。我们假设内源性的肿瘤坏死因子-α通过p55受体的信号途径，通过增强动脉壁炎症而慢性上调新生内膜的增殖。IL-10是一种抗炎细胞因子，是肿瘤坏死因子-α的主要内源性下调因子。初步研究表明，通过基因治疗的方式运送病毒IL-10可以减轻新生内膜的增生。利用遗传学、药理学和基因治疗的方法，我们将确定新生内膜增生是否受到IL-10依赖机制的调节，以及这一序列进行的细胞事件。我们假设Ill-10下调新生内膜的增殖。肿瘤坏死因子-α和白介素10介导的细胞过程是治疗阻断病理性动脉重塑的潜在部位。