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Defining Molecular Phenotypes of Exacerbation-Prone Asthmatics

Primary Objective

The Specific Aims of this program are to: 1. Define environmental determinants of asthma exacerbation in children. We will identify the environmental exposures that contribute to exacerbations (systemic corticosteroid courses, ER/urgent care visits, hospitalizations) in a cohort of exacerbation-prone urban children. The influence of asthma-relevant environmental exposures upon exacerbation-related outcomes (lung dysfunction, airway inflammation, severity, control) will be determined. Integrated biostatistical analyses will be used to define the main environmental determinants of exacerbations. The clinical outcomes will be further related to in vitro phenotypes of nasal epithelial cells and their susceptibility to rhinovirus (HRV) infections, the epigenetic landscape of CD4+ T cells, and the protective effects of pulmonary surfactant protein A (SP-A1 and SP-A2) and the lipids, palmitoyl-oleoyl-phosphatidylglycerol (POPG) and phosphatidylinositol (PI). 2. Identify transcriptomic and genetic signatures that correlate with exacerbation-prone phenotypes. We will focus on asthma endotypes characterized by high type 2 cytokine expression. Experimentation will compare gene expression profiles in nasal epithelial and sputum cells from different patient cohorts, to determine if these profiles can prospectively predict occurrence of asthma exacerbations. We will look for other molecular signatures in participant cells by using methods such as single cell sequencing, flow cytometry, and cell culture. Additional work will investigate interactions between high type 2 cytokines and the transcriptomic response of nasal epithelial cells to IL-13, environmental tobacco smoke and HRV infections. The influence of subject genotype upon HRV infections and the type 2 cytokine status will also be determined. Preliminary data identify SP-A, POPG and PI as endogenous molecules that can protect epithelial cells from HRV infection. Genotyping of the expressed SP-A repertoire will be used to determine the relationships between SP-A polymorphisms and exacerbation-prone phenotypes. 3. Identify the molecular programming of CD4+ T cells that drive pro-asthmatic immune activity in exacerbation-prone asthmatics. This Aim is designed to uncover the mechanisms of CD4+ T cell activity that contribute to exacerbation susceptibility. An integrated approach of epigenetic, chromatin, and transcriptional profiling will identify unique molecular signatures that can be used as potential biomarkers for exacerbation prediction, molecular targets for novel treatment, and molecular links to exacerbation-inducting environmental exposures and viral infections. Ex vivo analysis will test epigenetic and epithelial-immune-viral cross-talk regulation of CD4+ T cell activity associated with asthma exacerbations. 4. Elucidate the protective effects of pulmonary surfactant constituents (SP-A, POPG and PI) as antagonists of HRV infection and inflammation in exacerbation-prone asthmatics. Experiments in this Aim are designed to examine the activity of SP-A isoforms, POPG and PI as inhibitors of HRV infection and inflammatory cytokine production. The studies will reveal if nasal epithelial cells from different patient cohorts can be equally protected by surfactant constituents, or if subgroups possess intrinsic properties that prevent protection. Additional studies will determine the relationship between the expressed SP-A repertoire and exacerbations.

Study category: Healthy Volunteers

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Description

We want to learn more about asthma and how stuff in the air, like pollution and allergens, can make asthma worse in children. To do this we want to look at kids with and without asthma. If you join the study, you will participate in a remote consent visit, a clinic visit and a remote home visit. (Remote visits take place by video chat or phone.) Study activities include: breathing tests, surveys, blood draw, nasal cell and mucus collection, urine collection, sputum collection, home environmental testing, and wearing a small air monitor. The risks are minimal for participating in this research study. If needed, transportation to and from the clinic visit can be provided. You will be paid for your time and effort.

Details
Age

Child

Eligibility

To take part in this study, you need to be 8 to 17 years old and: Have asthma with severe asthma attacks, OR Have mild asthma with no severe asthma attacks in the last five years, OR Have no asthma

Phase

Not Applicable - Describes studies without FDA-defined phases, including studies of devices or behavioral interventions.

Type of Study

Observational

Scope

Local

Location

Childrens Hospital Colorado

Principal Investigator
Andrew Liu,  MD

Andrew Liu, MD

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