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Principal Investigator: Luis R Rodriguez
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $162,540
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <Active Oxygen><Acute><Address><Age><Aging><Alveolar><American><Architecture><Autophagocytosis><Autoregulation><Biogenesis><Biology><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cellular Metabolic Process><Chromatin><Chromatin Structure><Chronic><DNA Therapy><Data><Defect><Diagnosis><Diathesis><Disease><Disease Progression><Disease susceptibility><Disorder><Distal><Drugs><Dysfunction><Engineering / Architecture><Enzyme Gene><Enzymes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelial Cells><Epithelium><Event><FDA approved><Fibroblasts><Fibrosing Alveolitis><Fibrosis><Fibrotic lesions in lung><Foundations><Functional disorder><Gene Delivery><Gene Transfer Clinical><Genes><Genetic><Genetic Intervention><Goals><Homeostasis><Human><Impairment><In Vitro><Individual><Inflammatory><Injury><Intermediary Metabolism><Interstitial Lung Inflammation><Interstitial Pneumonia><Interstitial Pneumonitis><Interstitial Pulmonary Inflammation><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Knowledge><Life Expectancy><Ligands><Light><Link><Lung><Lung Alveolar Epithelia><Lung Diseases><Lung Respiratory System><Lung Tissue Fibrosis><Lung scar><Lung tissue scar><Measures><Medication><Mentors><Mesenchymas><Mesenchyme><Metabolic><Metabolic Processes><Metabolic dysfunction><Metabolic stress><Metabolism><Mice><Mice Mammals><Missense Mutation><Mitochondria><Modeling><Modern Man><Molecular><Murine><Mus><Myofibroblast><Organoids><Origin of Life><Oxygen Radicals><Pathogenesis><Patients><Pharmaceutical Preparations><Phenotype><Photoradiation><Physiological Homeostasis><Physiopathology><Population><Predisposition><Prevalence><Pro-Oxidants><Progenitor Cells><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Fibrosis><Pulmonary Scar><Pulmonary Surfactant Protein C><Pulmonary Surfactant-Associated Protein C><Pulmonary Surfactant-Associated Protein SP-C><Pulmonary Tissue fibrosis><Quality Control><Reactive Oxygen Species><Resolution><Role><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SP-C peptide><SP-C protein><Scarring at the lung><Scarring in the lung><Scientist><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severities><Severity of illness><Signal Transduction><Signal Transduction Systems><Signaling><Single cell seq><Source><Surfactant Polypeptide SP-C><Susceptibility><Telomere Shortening><Testing><Time><Training><Transitional Cell><Type I Cell><Type I Epithelial Receptor Cell><Type II Cell><Type II Epithelial Receptor Cell><Type II Pneumocyte><Viral><Work><Wound Repair><age associated><age associated alterations><age associated changes><age associated effects><age correlated><age correlated alterations><age correlated changes><age dependent><age dependent alterations><age dependent changes><age effect><age linked><age related><age related alterations><age related changes><age related effects><age specific><age specific alterations><age specific changes><aged><aged mice><aged mouse><ages><aging associated disease><aging associated mechanism><aging effect><aging mechanism><aging pathway><aging process><aging related disease><aging related mechanism><alterations with age><alveolar epithelium><alveolar homeostasis><alveolar type II cell><autophagy><biological mechanism of age><biological pathways of age><biological signal transduction><career><cell metabolism><cellular metabaolism><changes with age><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><cytokine><design><designing><diffuse interstitial pulmonary fibrosis><disease of aging><disease of the lung><disease severity><disorder of aging><disorder of the lung><drug/agent><elderly mice><epigenetically><epithelial progenitor><epithelial progenitor cell><epithelial stem cell><extracellular><fibrogenesis><fibrosis in the lung><fibrotic lung><gene repair therapy><gene therapy><gene-based therapy><genetic approach><genetic strategy><genetic therapy><genomic therapy><hiPSC><human data><human disease><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><iPS><iPSC><iPSCs><idiopathic pulmonary fibrosis><impact of age><in vivo><induced human pluripotent stem cells><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><influence of age><injuries><interest><interventional strategy><knockout gene><liability to disease><lung disorder><lung fibrosis><mitochondrial><mitochondrial metabolism><mortality><mouse model><murine model><mutant><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><old mice><pathophysiology><post-doctoral training><postdoctoral training><pre-clinical><preclinical><pro-aging><progenitor biology><progenitor cell biology><progenitor cell function><progenitor cell model><progenitor function><progenitor model><progeronic><promote aging><protein homeostasis><proteostasis><pulmonary><regenerative><resolutions><senescence><senescent><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><single cell next generation sequencing><single cell sequencing><social role><stem and progenitor biology><stem and progenitor cell function><stem and progenitor cell model><stem and progenitor function><stem cell based model><stem cell biology><stem cell derived model><stem cell function><stem cell model><stem cells><surfactant protein C><telomere attrition><wound healing><wound recovery><wound resolution>