# Effects of androgen receptor (AR) signaling on CD4+ T cell metabolism during airway inflammation

> **NIH NIH F30** · VANDERBILT UNIVERSITY · 2022 · $31,904

## Abstract

PROJECT SUMMARY/ABSTRACT
Severe asthma is difficult to control and accounts for the majority of asthma-related healthcare costs and
hospitalizations. Consistent with patterns of asthma, severe asthma rates are higher in women than men.
Severe, uncontrolled asthmatics may have airway inflammation mediated by a type 2, eosinophilic immune
response or may have increased neutrophilic driven airway inflammation driving by IL-17A and/or IFN-.
Testosterone, which signals through the androgen receptor (AR), decreases airway inflammation in mice.
Nebulized dehydroepiandrosterone-3-sulfate (DHEA-S), an androgen, improved asthma control in moderate to
severe asthma patients in a Phase II randomized clinical trial. However, the mechanisms by which AR
signaling decreases Th2 and Th17 driven airway inflammation in asthma remains unclear. My labs showed
that AR signaling decreased Th2 and Th17 driven inflammation and increased Treg stability in mice, that men
with severe asthma have significantly decreased circulating Th17 cells compared to women with severe
asthma, and that CD4+ T helper cells have distinct modes of metabolism, with Th17 and Th2 relying on
glutaminolysis and glycolysis metabolism and Tregs relying on oxidative phosphorylation. Further, my labs
previously showed increased glutaminolysis and glycolysis in bronchoalveolar lavage fluid from patients with
asthma and circulating T cells from patients with severe asthma had increased expression of markers of
glutaminolysis and glycolysis. My preliminary data shows that AR signaling decreases metabolic function
through reductions in glutaminolysis and glycolysis in mouse Th2 and Th17 cells. Additionally, male mice with
house dust mite (HDM) induced airway inflammation have decreased expression of enzymes related to
glutaminolysis compared to female mice. Recent studies showed that the let7 microRNA family reduced
glycolytic and glutaminolytic processes in B cells and CD8 T cells. Let7f, a member of the let7f miRNA family,
downregulated IL-17A and IL-23R expression in Th17, and our lab showed that ovarian hormones decreased
and 5α-DHT, an androgen, increased let7f expression in Th17 cells. Therefore, metabolic changes in T cells
could explain the change in the inflammatory milieu seen in severe, uncontrolled asthma. Based on these
findings, I hypothesize that AR signaling decreases glutaminolysis and glycolysis in T helper cells, resulting in
decreased Th2 and Th17-mediated airway inflammation. In this proposal, I will: (1) determine how AR signaling
decreases metabolism of T helper cells to limit airway inflammation, and (2) elucidate how AR signaling
promotes the negative regulation of let7f on T helper cell metabolism and differentiation. These studies will
demonstrate fundamental mechanisms by which sex hormones regulate CD4+ T cell biology as well as
uncover and provide evidence for new potential therapeutics, including DHEA-S or metabolic inhibitors such as
CB839, for patients with uncontrolled ...

## Key facts

- **NIH application ID:** 10534943
- **Project number:** 1F30HL159941-01A1
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Nowrin Umme Chowdhury
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $31,904
- **Award type:** 1
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10534943

## Citation

> US National Institutes of Health, RePORTER application 10534943, Effects of androgen receptor (AR) signaling on CD4+ T cell metabolism during airway inflammation (1F30HL159941-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10534943. Licensed CC0.

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