PROJECT 1: The pathogenesis of idiopathic pulmonary fibrosis (IPF) remains poorly defined;however, identificafion of mutafions 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 reficulum (ER) stress, acfivafion ofthe unfolded protein response, and cell death. We also show that ER stress occurs frequently in AECs in IPF, suggesfing that this pathway contributes to disease. In addifion, we show that herpesviruses are commonly localized to AECs in IPF and could contribute to ER stress and AEC injury. Finally, we have identified loss-of-funcfion 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. Identificafion of individuals in FIP families with early fibrotic changes will provide a valuable resource for invesfigafions aimed at defining primary disease mechanisms. In this study, we will ufilize CT scanning to identify asymptomafic individuals at risk for FIP who have radiographic changes consistent with early fibrosis. Subjects with eariy FIP and controls will undergo bronchoscopy for sample collecfion to test the following hypothesis. Genefic or acquired factors that increase the suscepfibility of lung epithelial cells to injury and/or apoptosis underiie the pathogenesis of IPF. Exposure of vulnerable epithelial cells to common injurious/toxic environmental sfimuli results in extensive injury with limited capacity for alveolar repair, leading to fibrofic remodeling. The following specific aims will invesfigate the role of AECs in early FIP: 1) to evaluate epithelial cell injury/apoptosis, markers of ER stress, and surfactant protein producfion in the lungs of pafients with eariy FIP, 2) to invesfigate whether herpesvirus infection occurs in eariy FIP, contributes to ER stress, and is associated with alveolar epithelial cell injury and, 3) to determine whether differenfial telomere length occurs in epithelial cells from patients with eariy FIP and correlates with epithelial cell injury. By elucidafing crifical components of eariy stage disease, our study will define novel therapeufic 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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|Kropski, Jonathan A; Young, Lisa R; Blackwell, Timothy S et al. (2017) Reply: The Genetic Diagnosis of Interstitial Lung Disease: A Need for an International Consensus. Am J Respir Crit Care Med 195:1539-1540|
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|Nevel, Rebekah J; Garnett, Errine T; Worrell, John A et al. (2016) Persistent Lung Disease in Adults with NKX2.1 Mutation and Familial Neuroendocrine Cell Hyperplasia of Infancy. Ann Am Thorac Soc 13:1299-304|
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