PROJECT 1: The pathogenesis of idiopathic pulmonary fibrosis (IPF) remains poorly defined;however, identification of mutations in the gene encoding surfactant protein C (SP-C) in the familial form of IPF (FIP), along with several other lines of evidence, suggests that alveolar epithelial cells (AECs) play a key role in disease progression. Our data indicate that abnormal processing of pro-SP-C by AECs leads to endoplasmic reticulum (ER) stress, activation ofthe unfolded protein response, and cell death. We also show that ER stress occurs frequently in AECs in IPF, suggesting that this pathway contributes to disease. In addition, we show that herpes viruses are commonly localized to AECs in IPF and could contribute to ER stress and AEC injury. Finally, we have identified loss-of-function mutations in telomerase genes that segregate with disease in some FIP families, suggesting that defective telomerase leads to telomere shortening and apoptosis of type II AECs. Identification of individuals in FIP families with early fibrotic changes will provide a valuable resource for investigations aimed at defining primary disease mechanisms. In this study, we will utilize CT scanning to identify asymptomatic individuals at risk for FIP who have radiographic changes consistent with early fibrosis. Subjects with early FIP and controls will undergo bronchoscopy for sample collection to test the following hypothesis. Genetic or acquired factors that increase the susceptibility of lung epithelial cells to injury and/or apoptosis underlie the pathogenesis of IPF. Exposure of vulnerable epithelial cells to common injurious/toxic environmental stimuli results in extensive injury with limited capacity for alveolar repair, leading to fibrotic remodeling. The following specific aims will investigate the role of AECs in early FIP: 1) to evaluate epithelial cell injury/apoptosis, markers of ER stress, and surfactant protein production in the lungs of patients with early FIP, 2) to investigate whether herpes virus infection occurs in early FIP, contributes to ER stress, and is associated with alveolar epithelial cell injury and, 3) to determine whether differential telomere length occurs in epithelial cells from patients with early FIP and correlates with epithelial cell injury. By elucidating critical components of early stage disease, our study will define novel therapeutic targets.
Interstitial lung diseases, including the idiopathic interstitial pneumonias, are a substanfial cause of morbidity and mortality for which there are no effective treatments. In this program, we will study the genetics and underlying biological mechanisms that lead to progressive fibrosis in the lungs. Our integrated approach will lead to new concepts in disease pathogenesis and identification of novel treatment strategies.
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