Project Grant K99HL171946

AGING AND METABOLIC DYSFUNCTION DRIVE DISRUPTED ALVEOLAR EPITHELIAL PROGENITOR FUNCTION IN PULMONARY FIBROSIS - ABSTRACT IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A FATAL LUNG DISEASE OF UNKNOWN CAUSE MARKED BY DYSFUNCTIONAL WOUND HEALING AND ABERRANT FIBROTIC REMODELING OF THE LUNG THAT CLAIMS THE LIVES OF MORE THAN 40,000 AMERICANS EACH YEAR. THE MEDIAN AGE OF IPF IS 66 YEARS AND PATIENTS HAVE AN AVERAGE LIFE EXPECTANCY OF 3 YEARS. THE SCIENTIFIC DISCOVERY INTO THIS DISEASE HAS BEEN SLOW AND HAS RESULTED IN ONLY TWO FDA APPROVED MEDICATIONS THAT DO NOT REVERSE OR CURE THE DISEASE. OUR EMERGING CONCEPTUAL UNDERSTANDING OF IPF HIGHLIGHTS THE SIGNIFICANT ROLE OF ALVEOLAR EPITHELIAL TYPE II CELL (AT2) CELL DYSFUNCTION IN UNDERLYING SUSCEPTIBILITY, DISEASE SEVERITY, AND DISEASE PROGRESSION. WE HAVE PREVIOUSLY DEMONSTRATED IN PRECLINICAL SFTPCI73T MURINE AND PATIENT- SPECIFIC INDUCED PLURIPOTENT STEM CELL (IPSC) MODELS A TIME DEPENDENT METABOLIC REPROGRAMMING PROMOTING A LOSS OF MITOCHONDRIAL FUNCTION IN THE AT2. OUR PRELIMINARY DATA HAS ALSO REVEALED THE EMERGENCE OF A RECENTLY CHARACTERIZED ABERRANT AT2 CELL STATED MARKED BY THE INABILITY TO COMPLETE DIFFERENTIATION INTO THE ALVEOLAR EPITHELIAL TYPE I CELL (AT1). FINALLY, AND RELEVANT TO THE OBSERVATION IN HUMANS, WE HAVE OBSERVED INCREASED MORTALITY AND INCREASED TRANSITIONAL CELL ACCUMULATION IN AGED SFTPCI73T MICE. TOGETHER THESE OBSERVATIONS SUGGEST A POTENTIAL LINK BETWEEN METABOLIC REPROGRAMMING, THE AGING PROCESS, AND AT2 PROGENITOR CELL BIOLOGY. THE BIOLOGY OF THIS ABERRANT PROGENITOR CELL WITHIN THE ALVEOLAR NICHE HAS BECOME A HIGH IMPACT QUESTION THAT REQUIRES FURTHER ELUCIDATION. TO ADDRESS THIS UNMET NEED, WE WILL UTILIZE AN AGED MURINE SFTPCI73T MODEL OF IPF THAT CLOSELY RECAPITULATES MANY ASPECTS OF THE HUMAN DISEASE AND PERMITS TEMPORAL MODELING OF SUBCLINICAL EVENTS IN ITS PATHOGENESIS. FURTHERMORE, WE WILL APPLY NOVEL GENETIC APPROACHES INCLUDING A LINEAGE TRACE MODEL OF THE AT2, MULTIPLE VIRAL CONSTRUCTS TO MANIPULATE KEY METABOLIC ENZYMES IN THE AT2, AND AN AT2 SPECIFIC MURINE MODEL ALLOWING US TO KNOCK OUT GENES OF INTEREST. FOUNDED IN THIS COMPELLING PRELIMINARY DATA, THE OVERALL GOAL OF THIS PROJECT IS TO IDENTIFY THE MECHANISM BY WHICH AGING INCREASES SUSCEPTIBILITY TO DISEASE PROGRESSION AND ALTERS ALVEOLAR HOMEOSTASIS. WE HYPOTHESIZE THAT THAT AGING EXACERBATES DEFECTS IN CELL QUALITY CONTROL AND METABOLISM TO DISRUPT AT2 PROGENITOR FUNCTION AND ENHANCE ABERRANT TRANSITIONAL CELL ACCUMULATION. WE WILL TEST THIS HYPOTHESIS IN TWO SPECIFIC AIMS: 1) IN-VIVO APPLICATION OF THE SFTPCI73T FIBROSIS MODEL TO CHARACTERIZE THE IMPACT OF AGING ON MITOCHONDRIAL QUALITY CONTROL AND METABOLIC DISRUPTION IN TRANSITIONAL AT2S THROUGHOUT FIBROGENESIS. 2) IN REDUCTIONIST SFTPCI73T MODELS, DETERMINE THE EFFECT OF AGING AND/OR SENESCENCE ON AT2 PROGENITOR CAPACITY, AT2-AT1 TRANSITION, AND THE AT2 PROFIBROTIC PHENOTYPE. 3) DEFINE THE ROLE OF AT2 DERIVED LACTATE ON AT2 TRANSITION CELL DYSFUNCTION AND FIBROTIC REMODELING IN AGED MODELS OF FIBROSIS THE FINDINGS FROM THIS STUDY WILL EXPAND OUR UNDERSTANDING OF AT2 PROGENITOR FUNCTION AND LINK AGE ASSOCIATED CHANGES WITH METABOLIC DYSFUNCTION IN IPF PATHOGENESIS. BEYOND THE SCOPE OF IPF, EPITHELIAL DYSFUNCTION IS A KEY ASPECT OF CHRONIC AND ACUTE LUNG DISEASE, PARTICULARLY IN LIGHT OF THE COVID-19 PANDEMIC.