Project Grant F30HL184508

MITOCHONDRIAL ADENINE NUCLEOTIDE TRANSLOCASE 2 (ANT2)-MEDIATED REGULATION OF IRON, FERROPTOSIS, AND LUNG REPAIR IN COPD - PROJECT SUMMARY/ABSTRACT CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) RANKS AS THE SIXTH LEADING CAUSE OF DEATH IN THE UNITED STATES. THIS CONDITION IS PRIMARILY MARKED BY CHRONIC INFLAMMATION, ALVEOLAR DESTRUCTION, REDUCED RENEWAL OF LUNG EPITHELIUM, AIRWAY REMODELING AND THICKENING, AND ABNORMALITIES IN LUNG EPITHELIAL CELLS, WITH CIGARETTE SMOKE IDENTIFIED AS A SIGNIFICANT RISK FACTOR. CURRENT TREATMENT OPTIONS FOR COPD ARE LIMITED, AND OUR UNDERSTANDING OF THE MECHANISMS UNDERLYING ALVEOLAR REPAIR REMAINS UNCLEAR. RECENT FINDINGS SUGGEST THAT MITOCHONDRIAL DYSFUNCTION AND IMPAIRED ALVEOLAR REGENERATION GREATLY CONTRIBUTE TO THE PATHOGENESIS OF COPD. MITOCHONDRIAL DYSFUNCTION, IRON DYSREGULATION, AND FERROPTOSIS WORSEN LUNG EPITHELIAL CELL INJURY AND IMPEDE REPAIR PROCESSES. THIS DYSFUNCTION DISRUPTS ENERGY PRODUCTION, INCREASES OXIDATIVE STRESS, AND INDUCES IRON OVERLOAD, PROMOTING ALVEOLAR CELL DEATH AND REDUCING CELL REGENERATION AND PROLIFERATION, ESPECIALLY IN ALVEOLAR PROGENITORS KNOWN AS ALVEOLAR TYPE 2 (AT2) CELLS. HOWEVER, THE MECHANISMS THAT CONNECT THESE PROCESSES IN COPD ARE NOT FULLY UNDERSTOOD. WE PROPOSE THAT ADENINE NUCLEOTIDE TRANSLOCASE 2 (ANT2), A MITOCHONDRIAL ADP/ATP TRANSPORTER, IS A CRITICAL LINK IN THESE PATHOLOGICAL PROCESSES. WITH SINGLE-CELL RNA SEQUENCING, ANT2 IS ENRICHED IN AT2 CELLS BUT IS DIMINISHED IN COPD PATIENTS' LUNGS COMPARED TO HEALTHY INDIVIDUALS. WE HYPOTHESIZE THAT THE LOSS OF ANT2 IN AT2 CELLS EXACERBATES METABOLIC CHANGES, IRON DYSREGULATION, AND FERROPTOTIC CELL DEATH, HINDERING LUNG REPAIR MECHANISMS. THE GOALS OF OUR PROPOSAL ARE TO (1) EXAMINE ANT2'S ROLE IN IRON REGULATION IN DYSFUNCTIONAL AT2 CELL RENEWAL AND (2) EVALUATE THERAPEUTIC TARGETING OF IRON OVERLOAD AND FERROPTOSIS CAN ENHANCE AT2 CELL REPAIR AND SLOW THE PROGRESSION OF COPD. WE WILL UTILIZE TRANSCRIPTOMIC DATASETS AND 3D ORGANOID CULTURE MODELS, USING AT2 CELLS FROM ANT2 KNOCKOUT MICE IN RELEVANT CIGARETTE SMOKE AND ELASTASE MODELS. THIS INVESTIGATION WILL UNDERSCORE THE IMPORTANCE OF MITOCHONDRIAL BIOLOGY IN COPD AND LUNG REGENERATION AND SUPPORT MY DEVELOPMENT AS AN INDEPENDENT PHYSICIAN-SCIENTIST FOCUSED ON PULMONARY MITOCHONDRIAL BIOLOGY THROUGH THE SCIENTIFIC, TECHNICAL, AND PROFESSIONAL SKILLS ACQUIRED DURING THIS TRAINING.