LUNG CONNECTIVE TISSUE--RESPONSES TO INJURY AND REPAIR

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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.