Asthma
Conditions
Keywords
Asthma
Brief summary
The purpose of this study is to examine the mechanisms of asthma. The investigators are comparing the cells of individuals with and without asthma and looking at the roles various parts of the cell play in the production and secretion of mucus.
Detailed description
The UCSF Airway Clinical Research Center has made longstanding and productive efforts to understand how type 2 immune responses in the airway act on epithelial cells to produce muco-obstructive pathology, a central feature of severe asthma and a major contributor to fatality from this disease. This center has made major contributions to identifying type 2 high asthma as the major asthma endotype, demonstrating that the type 2 cytokine IL-13 acts directly on airway epithelial cells to induce pathological changes in mucus, and showing that mucus plugging is a persistent feature of asthma that is associated with type 2 responses and with increased asthma severity. The overall objective of this proposal is to understand molecular mechanisms that account for alterations in secretory cell and mucus function that are important in severe asthma. The overarching hypothesis is that local type 2 immune responses induce IL-13-mediated changes in epithelial gene expression and that these changes, which involve several novel molecular mechanisms not previously explored, alter differentiation of secretory cells and production and secretion of mucins, leading to mucus plugging and airway obstruction. The proposal includes two highly related projects, each of which focuses on molecules and pathways that have previously unknown roles in secretory cell biology and mucus dysfunction. The proposed studies will provide new mechanistic insights that are highly relevant to the pathogenesis of severe asthma and may lead to novel therapeutic targets that address unmet needs.
Interventions
None listed
Sponsors
University of California, San Francisco
National Institute of Allergy and Infectious Diseases (NIAID)
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 Controls 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 * Asthmatics 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 |
|---|---|---|
| Quantitate mean gene expression of TSPAN8 in goblet cells from the airways of human asthma and health and report the mean for asthma and health (main outcome 1) and for both goblet cells and non-goblet cells in asthma. | Between 1-12 weeks | Specifically, gene expression will be interrogated in single cells via 10x droplet-based RNA sequencing of airway brushings obtained from bronchoscopy. The gene expression data is used to characterize individuals cells as goblet cells vs other cells. TSPAN8 is then quantitated via the data in these cells |
| Quantitate KRT8 in airway cells from human asthma vs health and report the mean level in the transitional secretory cell subset for both asthma and health. | Between 1-12 weeks | Using 10x droplet-based single-cell RNA sequencing, the investigators will interrogate expression in cells that are classified as a transitional secretory cell subset. The investigators will classify transcriptionally similar cells from airway brushings into discrete clusters using the single-cell RNA sequencing data from airway brushings obtained from bronchoscopy (Seurat4 package). The investigators will then map clusters to cell types and transitional states based on published human and mouse scRNAseq data from airway cells. Differentiation trajectories will be inferred using diffusion modeling (Monocle3 package) and analyze nascent versus mature mRNA expression (scVelo package). Investigators will then map KRT8 expression onto these cells and clusters. |
| Quantitate expression of miR-141/200 family members report mean expression for the transitional secretory cell population in human asthma vs health using methods similar to those in Outcomes 1 and 2. | Between 1-12 weeks | — |
Countries
United States
Contacts
CONTACTChristine P Nguyen, BS
PRINCIPAL_INVESTIGATORNirav Bhakta, MD, PhD
University of California, San Francisco
PRINCIPAL_INVESTIGATORPrescott Woodruff, MD, MPH
University of California, San Francisco
Outcome results
None listed