Asthma
Conditions
Keywords
Asthma
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.
Interventions
None listed
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
National Institute of Allergy and Infectious Diseases (NIAID)
University of California, San Francisco
Study design
Observational model
CASE_CONTROL
Time perspective
CROSS_SECTIONAL
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. | Between 1-12 weeks | We previously identified changes in epithelial gene expression in individuals with asthma. To identify candidate enhancers that account for these changes, we will use Drop-seq, ChIPseq and ATAC-seq to analyze freshly isolated airway epithelial cells from healthy controls and from well-characterized subjects with asthma. |
| Assessment of persistence of signatures of airway inflammation | 1-12 weeks and at 10-14 months | Perform epithelial brush gene expression profiling and sputum induction on longitudinal samples obtained at 12 months after the initial bronchoscopy, to assess stability of type-2 and non-type-2 pathways that are dysregulated in asthma. (Achieved via the PISA sub-study) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. | Between 1-12 weeks | Perform bronchoalveolar lavage (BAL) cell flow cytometry and epithelial brush gene expression profiling to look for non-type-2 pathways that are dysregulated in asthma. |
Countries
United States
Outcome results
None listed