Surfactant Protein C Mutations and Interstitial Lung Disease

Philadelphia Va Medical Center, Philadelphia PA

Investigators

Linked publications, trials & patents

Abstract

Idiopathic pulmonary fibrosis (IPF) a progressive scarring interstitial lung disease (ILD) that affects mainly older adults remains a significant unmet therapeutic need. The recent paradigm shift wherein the concepts of repetitive injury to a dysfunctional, vulnerable, alveolar epithelium coupled with an abnormal wound healing response serve as disease “drivers” is opening up new opportunities for therapeutic discovery in IPF. Over 60 mutations in the alveolar type 2 cell (AT2) restricted, Surfactant Protein C [SP-C] gene [SFTPC], have been found in sporadic and familial IPF and provide important clues for understanding IPF pathogenesis. Since its initial funding over 10 years ago, this Merit Review program has addressed the unmet need for veterans with IPF by leveraging two novel knock-in mouse models of spontaneous lung fibrosis which express clinical SP-C mutants in alveolar type 3 (AT2) epithelial cells in an inducible fashion to study IPF. The latest renewal (2021) received a 3%ile score and was awarded 8 years of funding as a Senior Clinician Scientist Investigator Award through 2029. This project is designed to interogate cell quality control and integrated stress responses to define key alveolar niche cell populations emerging during fibrogenesis and then assess the roles of endogenous endoplasmic reticulum (ER) stress and AT2 metabolic reprogramming in aberrant injury/repair pathways found in IPF. Using this successful and stable infrastructure, this supplement is responsive to VA RFA RD-22-029 in that its design will extend the scope of the parent Merit Review as well as promote diversity through support of the career development of an outstanding early stage investigator from an under-represented minority (Luis Rodriguez, PhD). The specific aims are designed to test the hypothesis that defects to cell quality control (macroautophagy; proteasome) disrupt AT2 metabolism and synergize with aging to disrupt AT2 progenitor function and accelerate senescence resulting in emergence of a pro-fibrotic niche in the distal lung. Scientific and technical feasibility is supported by the new preliminary data collected by Dr. Rodriguez that show: (i) Aged mice expressing mutant SPC have increased mortality as compared to younger mice (ii) AT2 cells in aged mice present with increased markers of cellular senescence (iii) Aged mice have an increased prevalence of AT2 transitional cells and (iv) AT2 transitional cells demonstrate increased metabolic dysfunction. The contemplated experimental approach will characterize synergism between multiple disrupted pathways associated with pulmonary fibrosis. In Aim 1 a doxycycline inducible SftpcI73T murine epithelial cell line will be used to evaluate the impact of senescence on AT2 cellular metabolism. Aim 2 leverages the availability of aged (>18-month-old) SftpcI73T IPF mice to determine the impact of aging and AT2 metabolic reprogramming on senescence and progenitor function (and vice versa). Our approach uses both reductionist and integrative models and offers the unique opportunity to comprehensively identify mechanisms and pathways promoting crosstalk between AT2 cells, inflammatory cells and fibroblasts that drive parenchymal remodeling. While the results achieved in this supplement will provide significant scientific impact to the field of IPF, of equal value will be its contribution towards achieving the objective of advancing diversity in the VA biomedical research workforce by providing critical infrastructure, data, and mentoring to support the next steps in career development of the proposed mentee punctuated by successful competition for a VA CDA.