Lung Connective Tissue-Responses to Injury And Repair

这个项目的中心主题是为了阐明肺对弹性蛋白酶损伤的反应机制，这是一种与慢性阻塞性肺病的临床发展相关的情况。我们的假设是，弹性酶诱导的肺组织降解导致弹性细胞活力的变化，其表型取决于弹性酶损伤的接近程度和持续时间，以及暴露于基质释放的生长因子和分泌的细胞因子。正常情况下，这些过程导致弹性蛋白的局部修复，而不会引起普遍的纤维化反应。然而，弹性蛋白的缺失结合基质结合生长因子和细胞因子的释放可导致弹性蛋白酶的慢性释放，导致弹性蛋白修复效率低下，随后破坏组织完整性。这项更新申请建立在上一个资助期的成就基础上，并提出扩展我们的假设，以获得肺对弹性蛋白酶损伤反应机制的新见解。为了探究这一中心主题，四个项目将用不同的实验设计从共同的概念目标出发，解决总体假设。四个项目提出了一种结合体外培养肺细胞了解机制和体内动物模型测试和进一步了解这些机制的综合方法。每个项目的目标和实验设计相互交织，以最大限度地交流专业知识和技术援助。福斯特博士将研究在与弹性蛋白酶损伤相关的情况下导致弹性蛋白基因转录上调的因素。Nugent博士将研究蛋白聚糖在调节基质结合生长因子的释放和受体结合中的作用。潘琴科博士将研究EGF受体信号在弹性酶诱导损伤中的作用。Goldstein博士将研究细胞因子、肿瘤坏死因子和白细胞介素1 β对弹性蛋白基因转录和细胞凋亡的影响。这四个项目将得到一个核心设施的支持，该设施将提供中央管理服务、细胞培养、显微分析、实施分析以及普通动物实验的实施和评估。总之，在要求的五年中，我们希望有助于理解导致肺气肿临床表现的病理事件的机制。

The central theme of this Program Project is directed toward elucidating mechanisms underlying the response of the lung to elastase injury-a situation clinically relevant to the development of COPD. Our hypotheses is that elastase-induced degradation of lung tissue results in a change in the viability of elastogenic cells and their phenotypic dependent on the proximity to and duration of elastase injury and exposure to matrix-released growth factors and secreted cytokines. Normally these processes result in localized repair of elastin without inducing a general fibrotic response. However, the loss of elastin combined with release of matrix bound growth factors and cytokines can lead to chronic release or elastase resulting in inefficient elastin repair and subsequent destruction of tissue integrity. This renewal application builds on the accomplishments of the last funding period and proposes to expand our hypotheses to gain new insights into mechanisms underlying the response of lung to elastase injury. To pursue investigation of this central theme four Projects will address the overall hypothesis from common conceptual objectives with different experimental designs. Al four projects propose an integrated approach that combines in vitro culturing of pulmonary cells to understand mechanisms and in vivo animal model to test and further understand these mechanisms. The aims and experimental design of each project are intertwined to allow maximum interchanges of expertise and technical assistance. Dr. Foster will investigate the factors responsible for transcriptional up-regulation of the elastin gene in situations related to elastase injury. Dr. Nugent will investigate the role of proteoglycans in modulating the release and receptor binding of matrix bound growth factors. Dr. Pancenko will study the role of EGF receptor signaling in elastase-induced injury. Dr. Goldstein will study the effects of the cytokines, tumor necrosis factor- and interleukin 1beta, on elastin gene transcription and cell apoptosis. The four Projects will be supported by a Core facility that will provide central administrative services, cell cultures, microscopic analyses, and the implementation analyses, and the implementation and assessment of common animal experiments. Together, over the requested five years, we hope to contribute to the understanding of the mechanisms that underlie t he pathological events leading to the clinical manifestations of emphysema.