- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01974180
Smoking-induced EGF-dependent Reprogramming of Airway Basal Cell Function
Study Overview
Status
Conditions
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.
Study Type
Enrollment (Actual)
Contacts and Locations
Study Locations
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New York
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New York, New York, United States, 10065
- Weill Cornell Medical College and Weill Cornell Medical Center, Department of Genetic Medicine
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Sampling Method
Study Population
Description
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
Study Plan
How is the study designed?
Design Details
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
EGF induced gene expression changes related to smoking-associated phenotypes
Time Frame: One year
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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.
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One year
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Collaborators and Investigators
Investigators
- Principal Investigator: Renat Shaykhiev, MD, PHD, Weill Medical College of Cornell University
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 1305013972
- Weill Cornell Medical College (Other Grant/Funding Number: Weill Cornell Medical College)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
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