INFLAMMATORY MECHANISMS OF NEOINTIMAL HYPERPLASIA

心血管疾病继续导致全国发病率，死亡率和成本数字。 新生内膜增生是许多这些疾病的基础病理生理学。 炎症与新生内膜增生和相关的动脉粥样硬化形成过程有关，尽管仍然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性事件。 目前的提案详细介绍了一个研究和培训计划，结合教学课程，质量互动与既定的调查，和一个假设驱动的机械研究计划。 此外，它还提供了细胞因子生物学，先进的免疫组织化学方法和基因治疗方法的新培训。该补助金经过深思熟虑，旨在帮助主要研究者实现作为学术血管外科医生进行独立调查的长期职业目标，并同时促进我们对新生内膜增生机制的了解。该培训计划的总体科学假设是，新生内膜增生通过炎症依赖机制进行。 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TNF-α导致新生内膜形成减少十倍。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）未知，将在本研究中定义。 由于TNF-α可以通过两种不同的受体，TNFRI（P55）和TNFRII（p75）的信号，我们将确定（使用遗传方法）通过哪种受体是TNF-α信号在动脉重塑的设置完成。 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，从而慢性上调新生内膜增生。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可减弱新生内膜增生。 使用遗传学，药理学和基因治疗方法，我们将确定是否新生内膜增生是由IL-10依赖性机制，以及细胞事件，这一序列的进展。 我们假设IL-10下调新生内膜增生。 TNF-α和IL-10介导的细胞过程作为治疗中断病理性动脉重塑的潜在位点。

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.