Idiopathic pulmonary fibrosis is a rare, progressive and largely untreatable group of disorders that affects up to 40,000 people in the United States. Current therapies are only effective in a minority of affected individuals. In this application we propose a high throughput proteomics effort aimed at identifying new molecular targets for therapeutic interventions in pulmonary fibrosis. We hypothesize that the unique phenotypic aspects of IPF: Temporal heterogeneity, lack of significant inflammation and abundance of myofibroblast foci represent a molecular disease mechanism specific to IPF. Therefore, identifying the unique proteomes that underlie these characteristics will lead to identification of novel rational molecular targets for intervention in IPF. We propose to use the recently introduced proteomics difference gel electrophoresis method (DIGE) to compare the proteomes of normal and fibrotic lungs and to apply the powerful methods of laser capture microdissection of immunofluorescently defined cells (IF-LCM) to compare the proteomes of specific cell types within normal and fibrotic regions in patients with idiopathic pulmonary fibrosis. We then propose to use advanced computational tools to integrate these results with our previous high throughput genomic studies to identify proteins that are key regulators of the disease process and to verify these results using IPF tissue microarrays. We assume that this approach will provide us with new molecular targets for therapeutic intervention in pulmonary fibrosis.
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