LUNG CONNECTIVE TISSUE--RESPONSES TO INJURY AND REPAIR

肺纤维组织中的弹性纤维和胶原纤维在 肺的结构和功能。 在这些结缔组织中 蛋白质与阻塞性和纤维化肺病有关。 这两种类型疾病的动物模型已被广泛用于 过去几十年来， 和纤维化病理学。 尽管这些研究提供了有用的 关于病原体和组织反应的信息， 这些反应的分子机制在很大程度上是未知的。 该计划的总体目标是确定调节机制， 肺结核结缔组织蛋白对条件的反应 模仿损伤/修复情况。 我们建议研究这些机制 使用肺成纤维细胞的体外模型， 研究细胞内和细胞外的调节反应， 从整个肺组织的复杂性到相对简单的细胞 培养体系 细胞培养的使用将使我们能够控制 损伤/扰动暴露的程度和修复/响应的参数。 参与的人员包括高级和初级教师以及 关键工作人员的经验和培训的概念和 生物化学、呼吸生理学和 分子，细胞和发育生物学是整合在我们的整个 提议的研究。 研究基础是建立在一个强大的核心上的 他们的专业知识和资源 一个独特而强大的团队，用于解剖肺部基础过程 结缔组织损伤和修复。 我们调查这些机制的计划分为五个， 综合项目。 项目1的重点是调节弹性蛋白和 在基质蛋白水解条件下的微纤维基因表达。 研究旨在探索降解产物、基质 和可能的内源性生长因子来控制上下波动- 原弹性蛋白mRNA水平的调节。 项目2侧重于机制 由此弹性蛋白和胶原蛋白基因表达被效应子下调， 物质. 总的目标是确定独联体的行动， 反式作用因子调节这种调节。 项目3重点是 伴随基质蛋白水解的细胞外弹性反应 使用各种蛋白酶和暴露条件。 研究旨在 确定弹性蛋白再合成（修复）的机制。 项目4重点 肽因子对赖氨酰氧化酶基因表达的调控， 改变其弹性蛋白和胶原蛋白表达的环境干扰物 印刷受体. 项目5的重点是各种肽单位的作用， 弹性蛋白原在引导和排列分子以形成不溶性的 弹性蛋白和弹性蛋白基因表达的调节。 这些项目 由三个核心单元支持， 培养物、分子、生物化学和免疫学探针、自动化 分析、显微镜检查和行政支助。

Elastic and collagenous fibers of lung interstitium play key roles in pulmonary structure and function. Abnormalities in these connective tissue proteins have been implicated in obstructive and fibrotic lung diseases. Animal models of both types of disease have been used extensively in the last several decades to define specific mechanisms underlying degradative and fibrotic pathologies. Although these studies have provided useful information regarding causative agents and tissue responses, the cellular and molecular mechanisms underlying these responses are largely unknown. The overall goal of this program is to determine the mechanisms regulating pulmonary interstitium connective tissue protein responses to conditions mimicking injury/repair situations. We propose to study these mechanisms using an in vitro model of pulmonary fibroblast cells where we can reduce studies of intra- and extracellular regulatory responses from the complexity of whole lung tissue to the relative simplicity of a cell culture system. The use of cell cultures will allow us to control the extent of injury/perturbant exposure and the parameters of repair/response. The personnel involved include both senior and junior faculty as well as key staff members whose experience and training in the conceptual and technological aspects of biochemistry, respiratory physiology and molecular, cellular and developmental biology are integrated throughout our proposed research. The research foundation is built upon a strong nucleus of established investigators whose combined expertise and resources create an unique and powerful team for dissecting processes underlying pulmonary connective tissue injury and repair. Our plan for investigating these mechanisms is divided among five, highly integrated projects. Project 1 focuses on the regulation of elastin and microfibril gene expression under conditions of matrix proteolysis. Studies are designed to explore the role of degradation products, matrix and possible endogenous growth factors in controlling up and down- regulation of tropoelastin mRNA levels. Project 2 focuses on mechanisms whereby elastin and collagen gene expression is down regulated by effector substances. The overall objective is to determine the actions of cis and trans acting factors in modulating this regulation. Project 3 focuses on the extracellular elastogenic responses that accompany matrix proteolysis using a variety of proteases and exposure conditions. Studies are aimed at determining mechanisms of elastin resynthesis (repair). Project 4 focuses on the regulation of lysyl oxidase gene expression by peptide factors and environmental perturbants that alter expression of its elastin and collagen substrates. Project 5 focuses on the role that various peptide units of tropoelastin play in directing and aligning the molecule to form insoluble elastin and in the regulation of elastin gene expression. These projects are supported by three core units which provide the essential cell cultures, molecular, biochemical and immunological probes, automated analyses, microscopy and administrative support.