# Dysregulated Immunometabolism and Premature Senescence in Corticosteroid-Refractory Severe Asthma

> **NIH NIH R35** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $725,426

## Abstract

Our laboratory has been engaged in elucidating mechanisms of asthma pathogenesis for over two decades.
These efforts resulted in the discovery of GATA-3 as the key molecular regulator of development of Th2 cells
that promote allergic airway disease. Since our initial discovery, GATA-3 was successfully targeted in allergen-
induced mild asthma in humans. While Th2-driven mild asthma is well recognized and therapeutically
manageable with inhaled corticosteroids (CS), 5-10% of asthma is clinically deemed severe and these patients
poorly respond to CS, even when used in large doses. To address this issue of disease heterogeneity and
identify the underlying mechanisms, we have studied the airway immune cells of severe asthma (SA) patients
using various tools of immunology and molecular biology including a high dimensional multi-omics approach.
Side-by-side we have used new mouse models of SA established in our laboratory to validate potential targets
for therapeutic intervention in vivo. These studies have led to another original and unexpected finding of a high
IFN-g response (Type 1/T1 response) in bronchoalveolar lavage (BAL) T cells in a subset of SA patients, a
large fraction of these T cells having features of tissue resident memory T cells (TRMs). A T1high immune
response is increasingly being appreciated in SA in both children and adults in independent studies
challenging the belief that IFN-g is always protective in asthma since it cross-regulates a T2 immune response.
We have also identified a deleterious feed forward positive loop induced by CS due to co-operation between
STAT1, downstream of IFN-g, and the glucocorticoid receptor (GR) that would cause unremitting IFN-g
production in the airways. The ramifications of unremitting IFN-g production can be profound and damaging
given its potential to induce cellular senescence. Intimately associated with the T1high immune response is also
cellular metabolism since mitochondrial dysfunction results in high levels of IFN-g production. Emerging
literature provides strong evidence of mitochondrial dysfunction in immune cells resulting in senescence and
inflammaging. While replicative senescence and inflammaging are typically associated with old age, the notion
of stress-induced premature senescence (SIPS) causing premature aging and decline is being entertained in
lung diseases including idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD).
Since IFN-g can induce senescence in surrounding cells, the driver of SIPS may be inflammatory immune
cells, especially T1high TRMs. The key goal of the proposed research program is to interrogate lung and
peripheral blood immune cells and lipids in the BAL fluid of patients to identify mechanisms that induce a CS-
refractory inflammatory phenotype in SA. We believe our studies would identify novel therapeutic targets to
prevent SIPS in SA which may have relevance in other lung diseases. The long-term funding and flexibility of
th...

## Key facts

- **NIH application ID:** 10772067
- **Project number:** 5R35HL166219-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Anuradha Ray
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $725,426
- **Award type:** 5
- **Project period:** 2023-02-01 → 2030-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10772067

## Citation

> US National Institutes of Health, RePORTER application 10772067, Dysregulated Immunometabolism and Premature Senescence in Corticosteroid-Refractory Severe Asthma (5R35HL166219-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10772067. Licensed CC0.

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