# Targeting T2 inflammation-evoked mechanical endotypes of ASM shortening in asthma

> **NIH HL R01** · RUTGERS BIOMEDICAL AND HEALTH SCIENCES · 2026 · $533,871

## Abstract

PROJECT SUMMARY:
Asthma is characterized by chronic inflammation and bronchial obstruction due to human airway smooth
muscle (HASM) shortening. However, the underlying basis for an enhanced shortening or the hyper-contractile
state of HASM in asthma is not known. Further, our incomplete understanding of type 2 (T2) inflammation-
regulated excitation-contraction (E-C) coupling in HASM shortening has hindered the development of new
HASM bronchodilators with a novel mechanism of action for over 60 years. This application seeks to gain a
foundational knowledge on the mechanical endotypes of HASM shortening in asthma (inflammation-dependent
and -independent) and identify improved bronchodilators that are less susceptible to tolerance and less
affected by immune inflammatory responses in asthma, focusing on previously unrecognized mechanisms
evoked by bitter taste receptors (TAS2Rs) expressed on HASM. Our preliminary data, in pre-clinical models,
support a premise that the immunologic and/or pathogenic mechanisms associated with a sustained
mechanical reinforcement of HASM shortening, and the loss of β2-adrenoceptor (β2AR)-mediated
bronchodilation, involve a transcriptional repressor function of the polycomb group (PcG) protein EZH2
(enhancer of zeste homolog 2). Further, our preliminary studies find a mechanistic role for microRNA-214
(miR-214) in TAS2R-evoked translational inhibition of EZH2. Based on these results, we hypothesize that
TAS2Rs on HASM inhibit T2 cytokine-regulated E-C coupling in HASM shortening and the physiological loss of
β2AR function in EZH2- and miR-214-dependent manners. Our goals are, first, to characterize T2- and non-T2-
mediated molecular kinetics and mechanics of E-C coupling in HASM shortening and, second, determine miR-
epigenetic nexus (i.e., non-genetic mechanisms) by which TAS2R activation promotes the functional efficacy of
β2ARs and inhibits the mechanical endotypes of HASM shortening in asthma. Toward this end, we will
leverage our un

## Key facts

- **NIH application ID:** 11311363
- **Project number:** 5R01HL164404-04
- **Recipient organization:** RUTGERS BIOMEDICAL AND HEALTH SCIENCES
- **Principal Investigator:** Steven S An
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** HL
- **Fiscal year:** 2026
- **Award amount:** $533,871
- **Award type:** 5
- **Project period:** 2023-06-25T00:00:00 → 2027-03-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11311363

## Citation

> US National Institutes of Health, RePORTER application 11311363, Targeting T2 inflammation-evoked mechanical endotypes of ASM shortening in asthma (5R01HL164404-04). Retrieved via AI Analytics 2026-05-20 from https://api.ai-analytics.org/grant/nih/11311363. Licensed CC0.

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