# Novel Molecular Mechanisms Promote GPCR-Induced Bronchodilation in Asthma

> **NIH NIH P01** · RUTGERS BIOMEDICAL AND HEALTH SCIENCES · 2022 · $76,612

## Abstract

Project Summary
 Our renewal of this interdisciplinary PPG remains focused on the theme of novel molecular mechanisms to
inhibit human airway smooth muscle (HASM) contraction and promote bronchodilation within the context of
airway inflammation and asthma. The principal hypothesis states that G protein coupled receptor (GPCR)
desensitization and unbiased signaling limits the efficacy of conventional bronchodilators, such that targeting
desensitization mechanisms, promoting biased agonism, circumventing mechanisms of ASM
hypercontractility/airway hyperresponsiveness (AHR), or engaging novel bronchorelaxant mechanisms in
HASM will provide superior therapy for asthma. Each Project addresses this hypothesis by either: 1) optimizing pro-
relaxant signaling abilities of one of 3 different GPCRs using strategies rooted in cutting edge biophysical or
pharmacological approaches; or 2) establishing novel intracellular targets mediating inflammation-driven AHR and
increased GPCR pro-contractile signaling.
 Project 1 will establish the mechanisms by which TGF-β1 modulates excitation-contraction (EC) coupling of
HASM and thereby identify novel therapeutic targets linked to both AHR and increased GPCR-mediated
contraction. Project 2 will advance the recent discovery of bitter taste receptors (TAS2R) as novel
bronchodilators clarifying the role of TAS2R subtypes in HASM, their mode of regulation and means to improve
their efficacy through biased agonism. Project 3 will characterize the molecular basis of β2AR biased signaling
to develop compounds that mediate Gs-biased signaling through either inhibition of β-arrestin interaction with the
agonist-occupied β2AR (arrestin-biased negative allosteric modulators (NAMs)) or by enhancing coupling of the
β2AR to Gs (biased orthosteric agonists). Project 4 will similarly characterize the mechanisms underlying biased
signaling of OGR1, develop new biased OGR1 benzodiazepine derivatives with superior ability to bronchodilate, and
determine the relative contribution of and mechanisms underlying peripheral benzodiazepine receptor activation by
candidate drugs.
 The four projects will be supported by Core A that will use high through-put screening of small molecule
libraries, whole genome, pooled shRNA libraries and virtual screening approaches to identify targets and
effectors of bronchodilation. Core B will provide all de-identified human cell and tissue models to study novel
mechanisms regulating EC coupling in HASM. Core C will provide administrative support for the program.
 The strengths of this Program are the common focus on a single theme and the productive working relationship among
investigators with the ability to apply cutting edge GPCR biology to key questions in asthma biology and pharmacology.

## Key facts

- **NIH application ID:** 10671828
- **Project number:** 3P01HL114471-09S2
- **Recipient organization:** RUTGERS BIOMEDICAL AND HEALTH SCIENCES
- **Principal Investigator:** Reynold Alexander Panettieri
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $76,612
- **Award type:** 3
- **Project period:** 2013-07-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10671828

## Citation

> US National Institutes of Health, RePORTER application 10671828, Novel Molecular Mechanisms Promote GPCR-Induced Bronchodilation in Asthma (3P01HL114471-09S2). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10671828. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*