Clinical trial NCT02791542: Sorting and Expression Profiling of Airway Cells From Humans (The SEARCH Study)
Official title: Sorting and Expression Profiling of Airway Cells From Humans (The SEARCH Study)
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Asthma
Keywords: Asthma
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2016-06-06
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Healthy and asthmatic participants recruited from community advertising

Brief summary: This will be a single site, mechanistic study of asthmatic subjects and healthy, non-asthmatic controls involving a baseline characterization visit and a research bronchoscopy visit. We will identify differences in airway epithelial epigenetic enhancer signatures in asthma, by analyzing freshly isolated airway epithelial cells from healthy controls and from well-characterized subjects with asthma.

Detailed description: The airway epithelium is critical for normal lung function and changes in the epithelium are central to the development of asthma. Precise regulation of gene transcription is essential for airway epithelial cell differentiation and transcription changes lead to many abnormalities seen in asthma. Despite the dominant role of enhancers in regulating transcription, little is known about how these DNA regulatory elements control airway epithelial cell transcription or about how enhancer activity differs in asthma compared to health. Closing this knowledge gap will have a major impact on our understanding of normal epithelial development and asthma. In addition, enhancer-based approaches for reprogramming the airway epithelium promise to be powerful tools for dissecting mechanism that will set the stage for developing a new class of precisely targeted treatments for asthma. Our overall goals are to identify enhancers that are important in regulation of key airway epithelial cell genes, to determine how enhancer activity changes in asthma, and to develop approaches for targeting the activity of these enhancers.

Eligibility criteria: Inclusion Criteria (Healthy participants):

1. Male and female subjects between the ages of 18 and 70 years
2. Ability to provide written informed consent and ability to comply with the requirements of the study
3. No hyperreactivity to methacholine (PC20 FEV1 Methacholine \>16 mg/mL)
4. No history of allergic rhinitis/seasonal allergies

Inclusion Criteria (Asthmatic participants):

1. Male and female subjects between the ages of 18 and 70 years
2. Ability to provide written informed consent and ability to comply with the requirements of the study
3. History of asthma
4. No use of oral or inhaled corticosteroids for the treatment of asthma during the past 6 weeks
5. Hyperreactivity to methacholine (PC20 FEV1 Methacholine \< 8 mg/ml)

Exclusion Criteria:

The same exclusion criteria will apply to both Sub-studies.

1. Current smokers, defined by (a) \>5 cigarettes smoked in past 12 months, and (b) ≤ 8 weeks since last time smoking; or former smokers who have a total smoking history ≥10 pack-years
2. Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study
3. Subjects with a history of lung disease other than asthma
4. Subjects with a history of a medical disease, which in the opinion of the Investigator may put the subject at extra risk from study-related procedures or because the disease may influence the results of the study
5. Prior esophageal hernia surgery.
6. Current participation in an investigational drug trial

Primary outcomes:
measure: Measure the genomic location of enhancers in genes previously found to be differentially expressed in asthma vs health using H3K27ac ChIP-seq and ATAC-seq on airway epithelial brushings.
timeFrame: Between 1-12 weeks
measure: Assessment of persistence of signatures of airway inflammation
timeFrame: 1-12 weeks and at 10-14 months
Secondary outcomes:
measure: Measure gene expression by RNA sequencing in both airway brushes and BAL cells for assessment of non-type-2 pathways differentially expressed in asthma vs health.
timeFrame: Between 1-12 weeks
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
Study officials:
affiliation: University of California, San Francisco
name: Nirav Bhakta, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco
name: Prescott Woodruff, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References: