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Principal Investigator: Suzanne M Cloonan
Organization: BAYLOR COLLEGE OF MEDICINE
Fiscal Year: 2024
Award: $796,760
Funding agency: National Heart Lung and Blood Institute
Abstract
We have previously shown that metformin, a biguanide commonly used for the treatment of type 2 diabetes, has
robust protective effects against cigarette smoke (CS)- induced lung pathologies including accelerated aging,
apoptosis, inflammation, and oxidative stress in mice and in individuals with emphysema-dominant COPD.
Alveolar epithelial cell injury contributes to structural damage in emphysema with alveolar type 2 epithelial (AT2)
cells crucial in promoting lung re-epithelization and maintenance of surfactant synthesis after such injuries. AT2
cells are the most metabolically active cells of the alveoli and use fatty acid oxidation (FAO, which occurs mainly
in mitochondria) as fuel. We here show that AT2 cells are the main target of metformin’s protective effects against
CS-induced lung damage, by reducing AT2 oxidative stress burden and improving AT2 FAO and mitochondrial
function. In this proposal, we will test the central hypothesis that metformin protects AT2 cells against CS-induced
dysfunction and emphysema by ameliorating dysfunctional AT2 cell mitochondrial metabolism and FAO. We will
also prove that, by improving FAO in AT2 cells, metformin rescues mitochondria from CS-induced dysfunction. To
test these hypotheses, we will pursue complementary Specific Aims. Aim #1 will test the hypothesis that
metformin improves AT2 function in a CS-induced emphysema model by partial binding of mitochondrial complex
1 (MTC) of the electron transport chain. Using CS-exposed mice lacking a functional MTC1 subunit, and +
metformin, we will analyze the effects of metformin on AT2 cell function by assessing mitochondrial function/stress,
and AT2 surfactant synthesis and regenerative functional capacity. In Aim #2, will test the hypothesis that
metformin improves AT2 function in a CS-induced emphysema model by restoring FAO improving lipid metabolism
and mitochondrial function in AT2 cells. Using CS-exposed mice lacking CPT1A, a key enzyme in FAO, and +
metformin, we will determine the protective effects of metformin on AT2 cell surfactant synthesis and regenerative
functional capacity by assessing lipid metabolism, FAO oxidation and mitochondrial function/stress. In Aim #3, we
will use fresh lung samples from individuals with COPD and controls recruited prospectively to confirm our
preclinical finding that metformin protects the lung against CS and COPD pathologies by ameliorating AT2 cell
FAO and mitochondrial impairment and thus AT2 cell function. Simultaneously, using fresh and frozen blood from
samples from the same patients and from well-characterized existing COPD patients’ cohorts, we will also
investigate the circulating lipidomic profile associated with the use of metformin as a marker of metformin efficacy
in a selected subset of COPD patients. The characterization of the effects of metformin on FAO in a preclinical
emphysema model, and in patients with emphysema will pave the way to new strategies targeting a selected
category of patients that could benefit from metformin treatment.
Terms: <Activities of Daily Living><Activities of everyday life><Adult-Onset Diabetes Mellitus><Alveolar><Alveolar Cell Type I><Alveolus><American><Apoptosis><Apoptosis Pathway><Assay><Autoregulation><Biguanides><Binding><Bioassay><Biological Aging><Biological Assay><Blood><Blood Reticuloendothelial System><Blood Sample><Blood specimen><Bronchial Alveolus><COPD><CPT 1><Carnitine Acyltransferase I><Carnitine O-Palmitoyltransferase><Carnitine Palmitoyltransferase><Carnitine Palmitoyltransferase I><Categories><Cell Aging><Cell Body><Cell Function><Cell Line><Cell Physiology><Cell Process><Cell Senescence><CellLine><Cells><Cellular Aging><Cellular Function><Cellular Physiology><Cellular Process><Cellular Senescence><Cellular injury><Chronic Obstruction Pulmonary Disease><Chronic Obstructive Lung Disease><Chronic Obstructive Pulmonary Disease><Cigarette smoke-induced emphysema><Clinical><Complex><D-Glucose><Data Set><Dextrose><Dimethylbiguanidine><Dimethylguanylguanidine><Disease><Disorder><Drug Targeting><Drug usage><Dysfunction><Electron Transport><Emphysema><Ensure><Enzyme Gene><Enzymes><Epithelial Cells><Epithelium><Fatty Acid Metabolism Pathway><Fatty Acids><Freezing><Functional disorder><Genetic><Genome Instability><Genomic Instability><Genus Hippocampus><Glucose><Hexadecanoates><Homeostasis><Immunofluorescence><Immunofluorescence Immunologic><Impairment><In Vitro><Individual><Inflammation><Injury><Isoforms><KO mice><Ketosis-Resistant Diabetes Mellitus><Knock-out Mice><Knockout Mice><Knowledge><Lipids><Lung><Lung Alveolar Epithelia><Lung Diseases><Lung Grafting><Lung Respiratory System><Lung Transplantation><Maintenance><Maturity-Onset Diabetes Mellitus><Measures><Metabolic><Metabolic Pathway><Metformin><Mice><Mice Mammals><Mitochondria><Mitochondrial DNA><Mitochondrial Proteins><Modeling><Molecular Interaction><Morphology><Murine><Mus><N,N-dimethyl-imidodicarbonimidic diamide><NIDDM><Natural regeneration><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Null Mouse><Operative Procedures><Operative Surgical Procedures><Oxidative Stress><Palmitates><Palmitoylcarnitine Transferase><Palmitylcarnitine Acyltransferase><Pathologic><Pathology><Patients><Phenotype><Physiological Homeostasis><Physiopathology><Pre-Clinical Model><Preclinical Models><Production><Programmed Cell Death><Protein Isoforms><Pulmonary Coin Lesion><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Emphysema><Pulmonary Graft><Pulmonary Pathology><Pulmonary Transplant><Pulmonary Transplantation><Randomized, Controlled Trials><Recommendation><Regeneration><Regenerative capacity><Regulation><Replicative Senescence><Respiration><Role><Sampling><Seahorse><Seminal><Slow-Onset Diabetes Mellitus><Solitary Pulmonary Nodule><Stable Diabetes Mellitus><Strains Cell Lines><Stress><Subcellular Process><Surgical><Surgical Interventions><Surgical Procedure><T2 DM><T2D><T2DM><TOPMed><Tamoxifen><Testing><Therapeutic><Trans-Omics for Precision Medicine><Type 2 Diabetes Mellitus><Type 2 diabetes><Type I Pneumocyte><Type II Diabetes Mellitus><Type II diabetes><Work><Yeasts><accelerated aging><accelerated biological age><accelerated biological aging><acylcarnitine><adult onset diabetes><age acceleration><alveolar epithelium><biological process of age><carnitine palmitoyltransferase 1><cell damage><cell injury><cellular damage><chronic obstructive pulmonary disorder><cigarette smoke><cigarette smoke exposure><cigarette smoke-induced><cigarette smoke-induced COPD><cigarette smoke-induced Chronic Obstructive Pulmonary Disease><cigarette smoke-induced lung damage><cigarette smoke-induced lung emphysema><cigarette smoke-induced lung injury><cigarette smoke-induced mitochondrial dysfunction><cigarette smoking><cigarette smoking-induced COPD><cigarette smoking-induced Chronic Obstructive Pulmonary Disease><cigarette use><cohort><conditional knock-out><conditional knockout><cultured cell line><daily living function><daily living functionality><damage to cells><disease of the lung><disorder of the lung><drug use><electron transfer><emphysematous><epithelial progenitor><epithelial progenitor cell><epithelial stem cell><exposure to cigarette smoke><fat metabolism><fatty acid metabolism><fatty acid oxidation><functional ability><functional capacity><hallmarks of aging><health-span><healthspan><healthy life span><improved><in vivo><injuries><injury to cells><ketosis resistant diabetes><life span><lifespan><lipid metabolism><lipidomics><lung disorder><lung function decline><lung pathology><lung transplant><maturity onset diabetes><mitochondrial><mitochondrial dysfunction><mitochondrial metabolism><mouse model><mtDNA><murine model><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><oxidation><pathophysiology><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><pillars of aging><pre-clinical><preclinical><prevent><preventing><progenitor><prospective><protective effect><proteomic signature><pulmonary><pulmonary function decline><randomized control trial><recruit><regenerate><regeneration ability><regeneration capacity><regeneration function><regenerative function><regenerative functionality><respiratory><respiratory mechanism><restoration><senescence><senescent><smoking-induced emphysema><social role><surfactant><surfactant production><surgery><type 2 DM><type II DM><type two diabetes>