Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

Smoking-induced EGF-dependent Reprogramming of Airway Basal Cell Function

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01974180
Recruitment Status : Terminated (Closed by investigator)
First Posted : November 1, 2013
Last Update Posted : December 26, 2017
Sponsor:
Information provided by (Responsible Party):
Weill Medical College of Cornell University

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 that epidermal growth factor receptor, known to regulate airway epithelial differentiation, is enriched in BC and its ligand EGF is induced by smoking, we hypothesized that smoking-induced EGF alters the ability of BC to form normally differentiated airway epithelium. To test this, airway BC will be purified using a cell-culture method established in our laboratory and responses to EGF will be analyzed using genome-wide microarrays and an in vitro air-liquid interface model of airway epithelial differentiation.

Condition or disease
Smoking COPD Chronic Obstructive Pulmonary Disease

Detailed Description:

Airway epithelium is composed of 4 major cell types, including ciliated cells, secretory cells, undifferentiated columnar cells, and basal cells (BC). The earliest changes associated with the development of smoking-induced lung diseases, such as chronic obstructive pulmonary disease (COPD) and lung cancer, occur in the airway epithelium, including BC hyperplasia, squamous metaplasia, mucous cell hyperplasia and metaplasia, impaired ciliated cell structure and function, loss of Clara cells, and increased epithelial permeability due to impaired junctional barrier. We hypothesize that fundamental to these changes are smoking-induced derangements of BC, the stem/progenitor cell population that can self-renew and differentiate into ciliated and secretory cells. Using technologies established in our laboratory to culture pure population of BC from the human airway epithelium, to induce differentiation of these BC in air-liquid interface, and to assess the transcriptome of purified BC compared to that of the complete differentiated airway epithelium, our preliminary data indicates that: (1) airway BC exhibit a distinct gene expression signature relevant to stem/progenitor cell function, including high expression of the epidermal growth factor receptor (EGFR); (2) airway BC from healthy smokers have a different gene expression pattern compared to nonsmokers, with enrichment of functional categories related to cell cycle and proliferation and down-regulation of differentiation-associated genes; and (3) constitutive EGF expression in BC and differentiated cells is barely detectable, but smoking selectively up-regulates EGF expression in differentiated cells of the airway epithelium in vivo. Based on these data and on the knowledge that EGFR signaling plays a central role in the regulation of cell proliferation and differentiation in the airway epithelium, the central concept of this proposal is that smoking-induced expression by differentiated cells activates BC via EGFR altering the molecular phenotype of airway BC and impairing their ability to generate normal differentiated airway epithelium. To assess this concept, the following aims will be addressed:

Aim 1. To determine whether stimulation of airway BC from healthy nonsmokers with EGF induces genes and pathways related to smoking-associated phenotypes, e.g. BC hyperplasia, squamous metaplasia, mucous metaplasia, abnormal cilia, decreased Clara cell number and compromised junctional integrity.

Aim 2. To test the hypothesis that stimulation of airway BC from healthy nonsmokers with EGF alters BC differentiation in air-liquid interface culture, with generation of smoking-associated phenotypes (see Aim 1).

Aim 3. To test the hypothesis that upon apical exposure to cigarette smoke extract, differentiated airway epithelial cells derived from BC of healthy nonsmokers release increased amounts of EGF into the apical supernatant, which will alter the ability of BC of healthy nonsmokers to generate normal differentiated airway epithelium, and that blocking EGF in this supernatant will abolish this effect.


Layout table for study information
Study Type : Observational
Actual Enrollment : 48 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Smoking-induced EGF-dependent Reprogramming of Airway Basal Cell Function
Actual Study Start Date : December 3, 2013
Actual Primary Completion Date : April 16, 2015
Actual Study Completion Date : April 23, 2015

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Smoking




Primary Outcome Measures :
  1. EGF induced gene expression changes related to smoking-associated phenotypes [ Time Frame: One year ]
    To determine whether stimulation of airway BC from healthy nonsmokers with EGF induces genes and pathways related to smoking-associated phenotypes, e.g. BC hyperplasia, squamous metaplasia, mucous metaplasia, abnormal cilia, decreased Clara cell number and compromised junctional integrity.


Biospecimen Retention:   Samples With DNA
Airway epithelial samples collected under IRB protocol #1204012331 will be used.


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
New York Metropolitan area residents
Criteria

Inclusion Criteria:

  • Must be capable of providing informed consent
  • Males and females, age 18 or older
  • 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

Exclusion Criteria:

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01974180


Locations
Layout table for location information
United States, New York
Weill Cornell Medical College and Weill Cornell Medical Center, Department of Genetic Medicine
New York, New York, United States, 10065
Sponsors and Collaborators
Weill Medical College of Cornell University
Investigators
Layout table for investigator information
Principal Investigator: Renat Shaykhiev, MD, PHD Weill Medical College of Cornell University

Layout table for additonal information
Responsible Party: Weill Medical College of Cornell University
ClinicalTrials.gov Identifier: NCT01974180     History of Changes
Other Study ID Numbers: 1305013972
Weill Cornell Medical College ( Other Grant/Funding Number: Weill Cornell Medical College )
First Posted: November 1, 2013    Key Record Dates
Last Update Posted: December 26, 2017
Last Verified: December 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Weill Medical College of Cornell University:
Smoking
COPD
Chronic Obstructive Pulmonary Disease
Healthy Smoker
Non-smoker

Additional relevant MeSH terms:
Layout table for MeSH terms
Lung Diseases
Lung Diseases, Obstructive
Pulmonary Disease, Chronic Obstructive
Respiratory Tract Diseases