Mechanisms of Familial Pulmonary Fibrosis

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DESCRIPTION (provided by applicant): This program has arisen from our long-standing interest in familial lung diseases, including familial interstitial pneumonia (FIP). We intend to use this unique cohort of families with FIP to investigate the underlying mechanisms that lead to progressive lung fibrosis. This information will be highly relevant to individuals with sporadic idiopathic pulmonary fibrosis (IPF) and other forms of idiopathic interstitial pneumonia (IIP). There are important advantages to investigating lung fibrosis in families. First, it is possible to study genetic causes of disease in this group. Three genes linked to disease, surfactant protein C and components of the telomerase complex, have already been identified using these FIP families, and this identification has led to new insights into disease pathogenesis. Second, this population allows us the unprecedented opportunity to identify pre-symptomatic patients that can be studied at the earliest stages of disease. This gives us the ability to study the primary manifestations of disease as opposed to pathobiological changes that occur as a result of progressive lung remodeling. Project 1 will identify pre-symptomatic individuals at risk for FIP families by high resolution CT scanning that have radiographic abnormalities in the lungs. At risk individuals (with and without radiographic abnormalities) will undergo bronchoscopy to identify phenotypic characteristics of alveolar epithelial cells, such as ER stress, herpesvirus infection, or telomere shortening that contribute to disease progression in FIP. Project 2 will utilize a candidate gene approach to identify and characterize rare genetic vanants in the surfactant and telomerase pathways, as well as genes known to be associated with secondary forms of pulmonary fibrosis, that impact development of FIP. Project 3 will perform a linkage study to discover new genetic loci associated with disease in FIP and sporadic MP patients. Additional studies will identify viruses present in lung tissue of patients with IIP and investigate gene-gene and gene-environment interactions that influence disease manifestation. The integrated approach in this Program will lead to new concepts in pathogenesis of FIP and sporadic IPF (as well as other forms of IIP), and suggest opportunities for novel treatment or prevention strategies.