Sorting and Expression Profiling of Airway Cells From Humans (The SEARCH Study)

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.

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. Current participation in an investigational drug trial