INFLAMMATORY MECHANISMS OF NEOINTIMAL HYPERPLASIA

新生内膜增生的炎症机制

• 批准号: 6190339
• 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/6190339
• 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、死亡率和费用数据中占据主导地位。 新内膜增生是许多这些疾病的潜在病理生理学。 炎症与新内膜增生和动脉粥样硬化形成的相关过程有关，尽管仍不确定动脉重塑是否通过炎症依赖性机制发生，或者炎症是否是继发事件。 当前的提案详细介绍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制研究计划。 此外，它还提供细胞因子生物学、先进免疫组织化学方法和基因治疗方法方面的新培训。该资助经过深思熟虑，旨在帮助首席研究员实现其作为一名学术血管外科医生进行独立研究的长期职业目标，同时增进我们对新生内膜增生机制的理解。该训练计划的总体科学假设是新内膜增生通过炎症依赖性机制进行。 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 在新内膜形成中的作用。 小鼠模型的初步研究表明，缺乏生物活性的 TNF-α 会导致新内膜形成减少十倍。这种 TNF-α 效应的时间顺序和细胞介质（白细胞和平滑肌细胞）尚不清楚，将在本研究中进行定义。 由于 TNF-α 可以通过两种不同的受体 TNFRI (P55) 和 TNFRII (p75) 发出信号，因此我们将（使用遗传方法）确定在动脉重塑过程中 TNF-α 信号传导通过哪个受体完成。 我们假设内源性 TNF-α 通过 p55 受体信号传导增强动脉壁炎症，从而长期上调新内膜增生。 IL-10 是一种抗炎细胞因子，是 TNF-α 的主要内源性下调因子。 初步研究表明，通过基因治疗方法递送病毒 IL-10 可减轻新内膜增生。 使用遗传、药理学和基因治疗方法，我们将确定新内膜增生是否受 IL-10 依赖性机制调节，以及该序列进行的细胞事件。 我们假设 Ill-10 下调新生内膜增生。 TNF-α 和 IL-10 介导的细胞过程是治疗性中断病理性动脉重塑的潜在位点。