# Evaluating the Impact of Metabolic Dysfunction on Asthma Pathology and Physiology

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $777,256

## Abstract

Project Summary/Abstract:
More than 40% of adult Americans are obese and obesity is common among patients with severe asthma. The
mechanisms underlying the association between obesity and severe asthma are poorly understood, but a clue
comes from the metabolic consequences of obesity, which include insulin resistance and systemic interleukin-6
inflammation. We recently showed that a subset of obese asthma patients have metabolic dysfunction (MD) and
that obese patients with MD have more severe asthma than obese patients without MD. In addition, we found
that lower lung function in obesity is more strongly related to measures of MD than measures of body mass
index. Furthermore, we found that obese patients with MD respond poorly to inhaled and systemic
corticosteroids. All of these findings lead us to hypothesize that obesity-related MD and insulin resistance causes
airway pathology that leads to corticosteroid resistant airway dysfunction. Here, we propose to test this
hypothesis by comprehensively characterizing airway physiology and pathology in obese asthma patients with
MD and exploring mechanisms by which insulin mediates airway dysfunction. We have 3 aims: Aim 1 will
characterize the radiographic and physiologic abnormalities in obese asthma patients with and without metabolic
dysfunction (MD). Here we will analyze computed tomography lung scans and perform cardiopulmonary exercise
testing in asthma patients with and without MD. We hypothesize that patients with MD have radiographic
measures of bronchial wall thickness and air trapping and suffer dynamic hyperinflation during exercise leading
to exercise intolerance. Aim 2 will characterize airway inflammation and airway remodeling in asthma patients
with metabolic dysfunction; Here, we will map the cellular profile of asthma patients with MD using transcriptomic
profiles from induced sputum samples and measure basement membrane zone thickness from endobronchial
biopsy samples to test our hypothesis that airway inflammation in obese patients with MD is type-2 low and that
these patients have airway remodeling characterized by subepithelial fibrosis. Aim 3 will develop gene
signatures of insulin-related airway disease and determine if these signatures are upregulated in asthma patients
with insulin resistance. Here we will utilize in vitro cell cultures and spatial transcriptomics to identify gene
expression signatures of insulin-mediated airway disease in airway fibroblasts and epithelial cells. We will then
determine if these gene signatures are upregulated in airway epithelial brushings or sputum cells from asthma
patients with IR. Together these aims will help address an important gap in knowledge about disease
mechanisms operating in obese patients with severe asthma and promises to provide data to inform novel
treatment approaches for these patients.

## Key facts

- **NIH application ID:** 10688260
- **Project number:** 5R01HL164787-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** John V Fahy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $777,256
- **Award type:** 5
- **Project period:** 2022-08-22 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10688260

## Citation

> US National Institutes of Health, RePORTER application 10688260, Evaluating the Impact of Metabolic Dysfunction on Asthma Pathology and Physiology (5R01HL164787-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10688260. Licensed CC0.

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