New Molecular Targets in Pulmonary Fibrosis

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

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Abstract

DESCRIPTION (provided by applicant): Idiopathic Pulmonary Fibrosis (IPF) is a progressive and largely untreatable group of disorders that affects up to 100,000 people in the United States Current proven therapies are only effective in a minority of affected individuals Despite the significant progress in understanding the general mechanisms that lead to pulmonary fibrosis in murine lungs, little is known about the molecular mechanisms and networks that determine the fibrotic pulmonary phenotype in IPF The research proposed is based on the hypothesis that the unique phenotypic aspects of IPF, temporal heterogeneity, lack of significant inflammation and abundance of myofibroblast foci, represent molecular mechanisms that are specific to IPF. Therefore, understanding the molecular networks that underlie these characteristics will lead to identification of novel rational molecular targets for intervention in IPF. This hypothesis will be tested by addressing the following specific aims: 1. To create a comprehensive expression profile of human pulmonary fibrosis. This will be achieved by identifying gene expression patterns that distinguish IPF from normal lung tissue and from other interstitial lung diseases, by identifying regional and temporal changes in gene expression and by identifying cell specific gene expression patterns in IPF lungs. 2. To identify "target" pathways and regulatory molecules that are candidates for therapeutic interventions using advanced computational methods This computational aimi includes: Determination of clinically relevant patterns of expression, identification of transcriptional regulation of observed expression patterns and generation of advanced computational methods that characterize gene expression "modules" and reconstruct "missing" key events in disease progression from gene expression data. 3. To verify protein expression levels of candidate molecules. This will be achieved by generating tissue arrays in which all interstitial lung diseases are represented. These arrays will be used for validation, frequency determination and cellular localization of abnormalities in protein expression of candidate molecules. 4. To identify the candidate molecules that affect "fibrosis related" cellular phenotypes using high throughout cell based assays. This will be done by assessing the effect of in-vitro inhibiting or inducing the expression of validated candidate molecules on ECM production and cytokine and growth factor secretion.