R35HL161169

Cell Competition in Pulmonary Fibrosis and ARDS - Idiopathic Pulmonary Fibrosis (IPF) is a common form of interstitial lung disease (ILD), resulting in alveolar remodeling and progressive loss of pulmonary function, respiratory failure, and death often within 5 years of diagnosis. Genetic and experimental evidence support the concept that chronic alveolar epithelial injury and failure to properly repair the respiratory epithelium are intrinsic to IPF disease pathogenesis.

HISTOLOGICALLY, RESPIRATORY EPITHELIAL CELLS IN THE LUNG PARENCHYMA ARE REPLACED BY CELLS WHICH ARE NORMALLY RESTRICTED TO CONDUCTING AIRWAYS. FIBROTIC LESIONS AND HONEYCOMB STRUCTURES REPLACE ALVEOLI, THE LATTER NORMALLY LINED BY ALVEOLAR TYPE 1 (AT1) AND AT2 CELLS.

Acute exacerbations by respiratory viral infections are the most devastating complication of IPF, having an in-hospital mortality rate of greater than 50%. Data from previous coronavirus pandemics such as Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS), as well as emerging data from the COVID-19 pandemic, suggest there could be substantial fibrotic consequences following SARS-CoV-2 infection, the causative agent of COVID-19.

INTERESTINGLY, THE MAJOR RISK FACTORS FOR SEVERE COVID-19 ARE SHARED WITH IDIOPATHIC PULMONARY FIBROSIS (IPF), NAMELY INCREASING AGE, MALE SEX, AND COMORBIDITIES SUCH AS HYPERTENSION AND DIABETES.

Although many patients who develop Acute Respiratory Distress Syndrome (ARDS) survive the acute phase of the illness, a substantial proportion die as a result of progressive pulmonary fibrosis. It remains unclear why certain individuals are able to recover from ARDS, whereas in others there is a shift to unchecked cellular proliferation with the accumulation of BC-PODs, fibroblasts, and myofibroblasts. In these patients, there is also excessive deposition of collagen alongside other components of the extracellular matrix resulting in progressive pulmonary fibrosis.

Distinct epithelial stem/progenitor cell pools and/or their mesenchymal niches repopulate injured tissue depending on the extent and type of injury, and the outcomes of regeneration or fibrosis in response to severe alveolar epithelial injury is dependent in part on the dynamics of cell competition between these cell populations.

IN TISSUES HARBORING A MOSAIC IMBALANCE IN CMYC OR YAP PROTEIN LEVELS, CELLS WITH HIGHER CMYC OR NUCLEAR YAP LEVELS BECOME SUPER-COMPETITORS AND EXPAND AT THE EXPENSE OF CELLS WITH LOWER LEVELS, BY ELIMINATING THEM. ALTERNATIVELY, IF CERTAIN STEM CELL POPULATIONS ARE SELECTIVELY WIPED OUT DUE TO THE TYPE OF INJURY, OTHER STEM CELL POPULATIONS THAT ESCAPE THE INJURY AND WHICH MAY NOT BE SO ADEPT AT REPLACING THE DESTROYED TISSUE WILL NOW HAVE A COMPETITIVE ADVANTAGE.

For example, SARS-CoV-2 enters respiratory epithelial cells via its receptor, Angiotensin-Converting Enzyme 2 (ACE2), causing severe airway and alveolar epithelial injury. Based on ACE2 expression, distinct stem/progenitor cell pools appear to be differentially susceptible to SARS-CoV-2 infection.

THIS GRANT PROPOSAL SEEKS TO MANIPULATE THE UNDERLYING MECHANISMS OF CELL COMPETITION TO HELP PREVENT AND TREAT IPF AND ARDS. CELL COMPETITION MIGHT ALSO BE EXPLOITED TO MAXIMIZE THE POTENTIAL OF HEALTHY TISSUE REPLACEMENT.

Mayo Clinic

THE DIVISION OF LUNG DISEASES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE CAUSES, DIAGNOSIS, PREVENTION, AND TREATMENT OF LUNG DISEASES AND SLEEP DISORDERS. RESEARCH IS FUNDED THROUGH INVESTIGATOR-INITIATED AND INSTITUTE-INITIATED GRANT PROGRAMS AND THROUGH CONTRACT PROGRAMS IN AREAS INCLUDING ASTHMA, BRONCHOPULMONARY DYSPLASIA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CYSTIC FIBROSIS, RESPIRATORY NEUROBIOLOGY, SLEEP AND CIRCADIAN BIOLOGY, SLEEP-DISORDERED BREATHING, CRITICAL CARE AND ACUTE LUNG INJURY, DEVELOPMENTAL BIOLOGY AND PEDIATRIC PULMONARY DISEASES, IMMUNOLOGIC AND FIBROTIC PULMONARY DISEASE, RARE LUNG DISORDERS, PULMONARY VASCULAR DISEASE, AND PULMONARY COMPLICATIONS OF AIDS AND TUBERCULOSIS. THE DIVISION IS RESPONSIBLE FOR MONITORING THE LATEST RESEARCH DEVELOPMENTS IN THE EXTRAMURAL SCIENTIFIC COMMUNITY AS WELL AS IDENTIFYING RESEARCH GAPS AND NEEDS, OBTAINING ADVICE FROM EXPERTS IN THE FIELD, AND IMPLEMENTING PROGRAMS TO ADDRESS NEW OPPORTUNITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Rochester, Minnesota 559050001 United States

Single Zip Code

NHLBI Outstanding Investigator Award (OIA) (R35 Clinical Trial Optional) (RFA-HL-20-011)

Amendment Since initial award the total obligations have increased 331% from $880,526 to $3,796,920.