R01HL166983

ANCILLARY SOURCE STUDY: CHARACTERIZATION OF SMALL AIRWAY BASAL CELL BIOLOGY IN EARLY COPD - ABSTRACT.

THIS IS AN ANCILLARY STUDY TO SOURCE (SPIROMICS STUDY OF EARLY COPD PROGRESSION, NHLBI HL144718), AN OBSERVATIONAL STUDY OF THE EARLY MANIFESTATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD).

BASED ON THE KNOWLEDGE THAT THE SMALL AIRWAY EPITHELIUM (SAE) IS THE EARLIEST SITE OF THE PATHOLOGY OF COPD, THE FOCUS OF THIS ANCILLARY PROPOSAL IS TO CHARACTERIZE THE DISORDERED SAE DIFFERENTIATION IN SOURCE PARTICIPANTS AND CORRELATE THIS BIOLOGIC DYSFUNCTION WITH THE ABNORMAL EARLY COPD SMALL AIRWAY CLINICAL PHENOTYPES CHARACTERIZED IN SOURCE.

WE WILL CAPITALIZE ON THE AVAILABILITY OF RESOURCES FROM SOURCE FOR USE IN OUR STUDY, INCLUDING: DETAILED CLINICAL PHENOTYPING OF SMALL AIRWAY STRUCTURE AND FUNCTION, WITH SERUM, LAVAGE FLUID, SAE CYTOPREPS, SAE RNA, AND SAE BASAL STEM/PROGENITOR CELLS OBTAINED BY BRONCHOSCOPY FROM N=80 INDIVIDUALS WITH EARLY COPD AGES 30-55, AND N=20 NORMAL CONTROLS.

AS AN ADDITIONAL CONTROL, WE WILL PROVIDE PARALLEL CLINICAL DATA AND BIOLOGIC SAMPLES FROM OUR BIOBANK N=10 HEALTHY SMOKERS.

BASED ON OUR OBSERVATIONS THAT IN EARLY COPD, SAE BASAL STEM/PROGENITOR CELLS HAVE A DECREASED CAPACITY TO FORM A NORMAL DIFFERENTIATED SAE, PRELIMINARY DATA DEMONSTRATING THAT BMP4 AND SPDEF ARE UPREGULATED IN THE SAE IN EARLY COPD SMOKERS AND THAT BMP4 INDUCES SQUAMOUS METAPLASIA AND SPDEF INDUCES GOBLET CELL HYPERPLASIA, THE PROPOSED STUDIES WILL CHARACTERIZE THE ROLE OF BMP4 AND SPDEF IN THE PATHOGENESIS OF THE DISORDERED SMALL AIRWAY DIFFERENTIATION IN EARLY COPD.

WE HYPOTHESIZE THAT EARLY COPD IS CHARACTERIZED, IN PART, BY SAE UPREGULATION OF BMP4 AND SPDEF WHICH, IN TURN, CONTRIBUTE TO THE CLINICAL ABNORMALITIES OF THE SMALL AIRWAYS THAT CHARACTERIZE EARLY COPD.

THE RESULTS WILL HELP DETERMINE IF BMP4 AND SPDEF AND/OR THEIR DRIVER GENES AND/OR DOWNSTREAM SIGNALING PATHWAYS ARE POTENTIAL TARGETS FOR FUTURE THERAPEUTIC INTERVENTION TO REVERSE/PREVENT THE SMALL AIRWAY ABNORMALITIES THAT CHARACTERIZE EARLY COPD.

WE PROPOSE 3 SPECIFIC AIMS.

AIM 1: TO CHARACTERIZE THE DISORDERED SAE IN EARLY COPD AND EVALUATE THE HYPOTHESIS THAT SAE BASAL CELLS (BC) FROM INDIVIDUALS WITH EARLY COPD HAVE A REDUCED CAPACITY TO DIFFERENTIATE INTO A NORMAL SAE AS ASSESSED IN VITRO USING AIR-LIQUID INTERFACE CULTURES.

AIM 2: TO EXAMINE THE HYPOTHESIS THAT THE DISORDERED SAE BC DIFFERENTIATION IN EARLY COPD IS CAUSED, IN PART, BY SAE OVEREXPRESSION OF BMP4 AND SPDEF, RESULTING IN ACTIVATION OF THEIR RESPECTIVE RECEPTOR DOWNSTREAM SIGNALING PATHWAYS AND CONSEQUENT ABNORMAL SAE DIFFERENTIATION OF SQUAMOUS METAPLASIA AND GOBLET CELL HYPERPLASIA.

AIM 3: TO TEST THE HYPOTHESIS THAT DIMINISHED SMALL AIRWAY EPITHELIAL BC DIFFERENTIATION AND BMP4- AND SPDEF- MEDIATED BIOLOGIC PARAMETERS CORRELATE WITH THE CLINICAL PARAMETERS OF SMALL AIRWAY STRUCTURE AND FUNCTION IN THE SAME SOURCE PARTICIPANTS WITH EARLY COPD.

Weill Medical College Of Cornell University

NOT APPLICABLE

93.837 - Cardiovascular Diseases Research

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

New York, New York 100654805 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 299% from $799,965 to $3,193,611.