# Identification of Th17 Metabolic Pathways that Contribute to Glucocorticoid Resistance in Asthma

> **NIH NIH F31** · VANDERBILT UNIVERSITY · 2020 · $25,872

## Abstract

SUMMARY
T effector (Teff) cells induce and require glycolytic pathways and increase their uptake of glucose to have
energy for activation and proliferation. Teff cells, specifically Th2 and Th17 subsets, are found in the airway
inflammation present during asthma. As disease increases in severity, there is a shift to an IL-17 predominant
and highly Th17-enriched response. Treatments of asthmatic patients include the use of glucocorticoid (GC)
steroids. These drugs are effective at controlling inflammation in mild cases, but Th17 cells have been shown
to have an intrinsic resistance to GCs and their increasing abundance in severe asthma contributes to a
general resistance of these patients to GC treatment. A key therapeutic objective, therefore, is to identify
mechanisms that contribute to Th17 resistance to GC and targets that may be exploited to increase sensitivity
of Th17 cells to GCs. One potential target may be cell metabolism. GCs are well known to modulate
metabolism and our preliminary studies show GC to decrease mitochondrial capacity. Further, studies have
shown that cells that have increased glycolysis and oxidative phosphorylation are more resistant to the effects
of GCs. The Rathmell lab including my preliminary data has now shown through biochemical approaches that
Th17 cells have a unique metabolism in that they are glycolytic and have a high mitochondrial capacity which
is fueled by glucose and glutamine metabolism and may contribute to the intrinsic resistance of these cells to
GCs. We propose to identify metabolic pathways that are altered in airway inflammation and in GC-resistant T
cells. We hypothesize that high levels of glycolysis in T cells are essential for airway inflammation in
asthma and that Th17 cells promote GC resistance due to their greater mitochondrial oxidative
capacity and higher use of glutaminolysis. Greater flux through these pathways would increase the ability
of Th17 cells to manage metabolic and oxidative stress. However, the in vivo metabolism of Th2 and Th17
cells that may contribute to disease remains poorly understood. To better understand T cell metabolism and
test our hypothesis, we will: (1) Determine if differences in the metabolic programs of Th2 and Th17 cells drive
their response in a mouse model of airway inflammation and (2) Identify the effects of glucocorticoids on the
metabolic programming of Teff cells in a mouse model of airway inflammation. Our goal is to test a potentially
new mechanism of GC resistance in asthma in which the metabolism of Th17 cells contributes to therapy-
resistance. These studies will establish the key metabolic targets that may contribute to GC-resistance in Th17
cells during airway inflammation to ultimately identify new targets to increase GC-sensitivity in those cells.

## Key facts

- **NIH application ID:** 9935136
- **Project number:** 5F31HL142189-03
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Diana C Contreras Healey
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $25,872
- **Award type:** 5
- **Project period:** 2018-06-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9935136

## Citation

> US National Institutes of Health, RePORTER application 9935136, Identification of Th17 Metabolic Pathways that Contribute to Glucocorticoid Resistance in Asthma (5F31HL142189-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9935136. Licensed CC0.

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