Ignite Creation Date:
2024-05-06 @ 2:08 AM
Last Modification Date:
2024-10-26 @ 11:14 AM
Study NCT ID:
NCT01974180
Status:
TERMINATED
Last Update Posted:
2017-12-26
First Post:
2013-10-25
Brief Title:
Smoking-induced EGF-dependent Reprogramming of Airway Basal Cell Function
Sponsor:
Weill Medical College of Cornell University
Organization:
Weill Medical College of Cornell University
Study Overview
Official Title:
Smoking-induced EGF-dependent Reprogramming of Airway Basal Cell Function
Status:
TERMINATED
Status Verified Date:
2017-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Closed by investigator
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Early changes associated with the development of smoking-induced diseases eg COPD and lung cancer the two commonest causes of death in US are often characterized by abnormal airway epithelial differentiation Airway basal cells BC are stemprogenitor 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
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 stemprogenitor 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 stemprogenitor 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 eg 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
Aim 1 To determine whether stimulation of airway BC from healthy nonsmokers with EGF induces genes and pathways related to smoking-associated phenotypes eg 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| Weill Cornell Medical College | OTHER_GRANT | Weill Cornell Medical College | None |