# S-glutathionylation chemistry, glycolysis and obese allergic asthma

> **NIH NIH R01** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2020 · $532,400

## Abstract

PROJECT SUMMARY
Obese asthma represents an important clinical problem due to the growing number of affected patients
worldwide, and their disease severity which is poorly controlled with existing medications. Changes in
metabolism, and associated changes in redox homeostasis are believed to contribute to obesity-associated
diseases. This project addresses whether S-glutathionylation chemistry (PSSG, a redox-based modification of
protein cysteine residues involving conjugation with glutathione) contributes to the pathogenesis of obese allergic
asthma. We have discovered a close association between PSSG chemistry and glycolysis in lungs from mice
with house dust mite (HDM)-induced allergic airways disease, and in primary nasal epithelial cells from
asthmatics. Redox proteomics identified he glycolytic enzyme, pyruvate kinase M2 (PKM2) as an important
target for S-glutathionylation. PKM2 had recently been implicated in the augmentation of pro-inflammatory
responses. Importantly, both PSSG and glycolysis were increased in settings of obesity, suggesting that PSSG
and linked alterations in glycolysis may be a key feature of obese allergic asthma. These findings led us to
hypothesize that glycolysis is a critical process that promotes allergic airways disease, and that this process is
enhanced by S-glutathionylation of the glycolytic enzyme PKM2 (PKM2-SSG). We furthermore hypothesize that
these processes are augmented in obese asthmatic individuals compared to lean allergic asthmatics. Avenues
to inhibit glutathione S-transferase P (GSTP, a catalyst of S-glutathionylation) or to promote de-glutathionylation
of PKM2 by increasing expression of the de-glutathionylating enzyme, glutaredoxin-1 (GLRX), are anticipated to
attenuate glycolytic reprogramming and to decrease airways disease in obese allergic asthmatics. In Specific
Aim #1 we will determine the impact of genetic ablation or inhibition of GSTP in decreasing glycolysis in mice
house dust mite (HDM)- diet induced obesity (DIO)- mediated lung disease, and in nasal epithelial cells from
lean and obese allergic asthmatics. In Specific Aim #2 we propose to assess the impact of modulation of GLRX
in lung tissues in order to attenuate PSSG, PKM2-SSG, and glycolysis in settings of lean or obese allergic
airways disease. We will utilize transgenic approaches or administer recombinant GLRX directly into airways of
lean or obese mice with existing allergic airways disease. Specific Aim #3 addresses the importance of pyruvate
kinase M2 for lean or obese allergic airways disease. We will specifically ablate the Pkm2 gene from airway
epithelial cells in mice and propose pharmacological approaches to enhance PKM2 activity in mice with existing
HDM/DIO-induced allergic disease and in nasal epithelial cells derived from lean or obese healthy subjects or
asthmatics. Completion of the proposed studies will provide new mechanistic insights into how S-
glutathionylation facilitates glycolytic reprogramming and has the...

## Key facts

- **NIH application ID:** 9968384
- **Project number:** 5R01HL137268-04
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** Anne E Dixon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $532,400
- **Award type:** 5
- **Project period:** 2017-08-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9968384

## Citation

> US National Institutes of Health, RePORTER application 9968384, S-glutathionylation chemistry, glycolysis and obese allergic asthma (5R01HL137268-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9968384. Licensed CC0.

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