Defective FGFR2 Signaling in the Small Airway Basal Progenitor Cells in COPD

NCT02341326 | Completed

• 2 other identifiers: 1311014509R01HL123544
• Study Type: observational
• Target: 111
• Locations: 1 country
• Sites: 1

Brief Summary

Early changes associated with the development of smoking-induced diseases, e.g., COPD and lung cancer (the two commonest causes of death in U.S.) are often characterized by abnormal airway epithelial differentiation. Airway basal cells (BC) are stem/progenitor cells necessary for generation of differentiated airway epithelium. Based on our preliminary observations on SAE BC cells and FGFR2 signaling, we hypothesized that suppression of FGFR2 signaling in the SAE BC stem/progenitor cells by cigarette smoking renders these cells less potent in generating and maintaining normally differentiated SAE, shifting these cells towards a COPD associated phenotype. To test this, SAE basal cells will be isolated from cultured cells obtained through bronchoscopic brushings and analyzed through in vitro assays for their stem/progenitor capacities.

Conditions

COPD; Smoking; Lung Disorder

Keywords

Lung; COPD; smoking; Non-smoker

Outcome Measures

Primary Outcomes (1)

• Expression of FGFR2 and related pathways in SAE BC

  Measure of Expression of FGFR2 and related pathways in SAE BC

  5 Years

Study Arms (3)

Healthy nonsmokers

n=20 for Aim 1 n=20 for Aim 2 Aim 1.To determine whether BC from the SAE of COPD smokers have reduced capacity to generate normally differentiated SAE, e.g initiate airway branching and repair in response to injury in vitro but generate airway epithelium with the phenotype similar to that present in SAE of COPD smokers in vivo. Aim 2.To test the hypothesis that FGFR2 signaling is necessary for normal SAE BC stem cell function and suppression of FGFR2 caused by inhibitors and smoking associated factors (EGF and TGF- beta)leads an altered stem cell functional phenotype similar to SAE BC from COPD smokers with reduced capacity as characterized by Aim 1.

Healthy smokers

n=20- for Aim 1 n=20 for Aim 3 Aim 1.To determine whether BC from the SAE of COPD smokers have reduced capacity to generate normally differentiated SAE, e.g initiate airway branching and repair in response to injury in vitro but generate airway epithelium with the phenotype similar to that present in SAE of COPD smokers in vivo. Aim 3.To assess the hypothesis that increasing FGFR2 signaling and suppressing smoking induced EGF receptors and TGF-beta pathways will restore the FGFR2 expression and normalize the capacity of SAE BC stem cells to generate and maintain normally differentiated SAE.

COPD smokers

n=20- for Aim 1 n=20 for Aim 3 Aim 1.To determine whether BC from the SAE of COPD smokers have reduced capacity to generate normally differentiated SAE, e.g initiate airway branching and repair in response to injury in vitro but generate airway epithelium with the phenotype similar to that present in SAE of COPD smokers in vivo. Aim 3.To assess the hypothesis that increasing FGFR2 signaling and suppressing smoking induced EGF receptors and TGF-beta pathways will restore the FGFR2 expression and normalize the capacity of SAE BC stem cells to generate and maintain normally differentiated SAE.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

New York Metropolitan area residents

You may qualify if:

• Must be capable of providing informed consent
• Males and females, age 18 or older
• Nonsmoking, matched with other groups by age, sex, ethnic/racial group
• Good overall health without history of chronic lung disease, including asthma, and without recurrent or recent (within 3 months) acute pulmonary disease
• Normal physical examination
• Normal routine laboratory evaluation, including general hematologic studies, general serologic/ immunologic studies, general biochemical analyses, and urine analysis
• Negative HIV serology
• Normal chest X-ray (PA and lateral)
• Normal electrocardiogram
• Females - not pregnant
• No history of allergies to medications to be used in the bronchoscopy procedure
• Not taking any medications relevant to lung disease or having an effect on the airway epithelium
• Willingness to participate in the study

You may not qualify if:

• Pregnancy
• Current active infection or acute illness of any kind
• Current alcohol or drug abuse
• Evidence of malignancy within the past 5 years

Sponsors & Collaborators

• Weill Medical College of Cornell University: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (1)

Weill Cornell Medicine

New York, New York, 10021, United States

Location

Biospecimen

Retention: SAMPLES WITH DNA

De-identified secondary lung tissue samples from deceased individuals (smokers or nonsmokers) with COPD or without COPD (normal lung donors without history of chronic lung disease) obtained via collaboration with Dr. Scott Randell, U North Carolina.

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive; Smoking; Lung Diseases

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Behavior

Study Officials

• Renat Shaykhiev, MD

  Weill Cornell Medical College, NY

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 16, 2014
• First Posted: January 19, 2015
• Study Start: July 1, 2014
• Primary Completion: October 29, 2024
• Study Completion: October 29, 2024
• Last Updated: March 11, 2025

Record last verified: 2025-03

Locations

US (1)