# Scientific innovation for personalized severe asthma management

> **NIH NIH P01** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $2,409,373

## Abstract

PROJECT SUMMARY/ABSTRACT
Our overall goal is to characterize the cell biology and physiology of recently identified mechanisms underlying
severe asthma. Severe asthma is a disabling obstructive lung disease that accounts for the majority of the
morbidity and mortality associated with asthma; it accounts for annual healthcare costs in excess of $10 billion
in the United States alone. Severe asthma has been a particular focus of our therapeutic development efforts.
We have discovered and studied three novel mechanisms relevant to severe asthma. These include the role in
severe asthma of: 1) β2 adrenergic receptor regulation by S-nitrosylation; 2) airway acidification; and 3) androgen
signaling. Each of these three mechanisms has the potential to be treated with novel, personalized therapies
that will be studied in a complementary fashion in the third Aim of each Project. Three synergistic proposed
Projects are proposed: Project 1, S-nitrosylation signaling in severe asthma; Project 2, airway pH regulation in
severe asthma; and Project 3, androgen signaling in severe asthma. Note that a substantial amount of the
science, and most of the proposed Cores, are currently incorporated in an NHLBI –sponsored Translational P01
at our two institutions, Indiana University and Case Western Reserve University. However, the NHLBI is not
planning to renew its Translational P01 initiative. What this means for the current proposal, however, is that the
scientific interface, as well as the Cores, are currently operational; and they are not duplicated at either institution.
We propose to continue these Core functions in the current proposal. The three Projects have scientific
synergy. For example, detrimental denitrosylation (Project 1) is reversed both by airway alkalinization (Project
2) and by airway epithelial androgen treatment (Project 3). Interleukin 17, which decreases airway epithelial S-
nitrosothiol signaling (Project 1) is inhibited by airway alkalinization (Project 2) and androgen receptor signaling
(Project 3). Interleukin 4 gene expression appears to be inhibited both by human airway alkalinization (Project
2) and by androgen receptor signaling (Project 3). These and related interactions will be studied in detail. The
Program also has robust operational synergy. Each Project will make use of each core. In particular, each
will use data and specimens from the Research Bronchoscopy and Biospecimens Core and from the Severe
Asthma Clinical Trials Core; each will use cells from the Primary Human Airway Cell Culture Core; each will rely
heavily on the Pulmonary Biostatistics Core for data analysis; and all projects and cores will be coordinated by
an Administrative Core. Note that the Administrative Core will also assist all Projects with data dissemination,
with speakers and with advisory boards. None of the three Projects would be able to support these Core
functionalities as an independent R01. At the conclusion of this Program, we anticipate having used...

## Key facts

- **NIH application ID:** 10457990
- **Project number:** 5P01HL158507-02
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Benjamin Gaston
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,409,373
- **Award type:** 5
- **Project period:** 2021-08-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10457990

## Citation

> US National Institutes of Health, RePORTER application 10457990, Scientific innovation for personalized severe asthma management (5P01HL158507-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10457990. Licensed CC0.

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