# Project 4 - OGR1- and TSPO- dependent mechanisms mediated by benzodiazepines affecting ASM contraction

> **NIH NIH P01** · RUTGERS BIOMEDICAL/HEALTH SCIENCES-RBHS · 2021 · $373,143

## Abstract

Project Summary
 In the previous cycle we characterized the ability of certain benzodiazepines, in cooperation with decreased
extracellular pH, to regulate airway smooth muscle (ASM) signaling and function via activation of the proton-
sensing G protein-coupled receptor (GPCR) OGR1 (Ovarian cancer G-protein coupled receptor 1 aka GPR68).
Importantly, we discovered that the multiple signaling pathways activated downstream of OGR1 could be
selectively activated (i.e., biased) to produce differential effects on ASM contraction and proliferation. In this
second cycle we propose to: 1) delineate the mechanisms by which the biasing of OGR1 signaling occurs; 2)
detail an additional, mitochondrial-dependent effector arm of benzodiazepines that also inhibits ASM contraction;
and 3) employ modeling to develop more efficacious benzodiazepine-like drugs that target these mechanisms.
These goals will be achieved through 3 Specific Aims. In Aim 1 we will employ cell-based and integrative models
of ASM contraction to clarify the how different benzodiazepines promote specific OGR1- and peripheral
benzodiazepine receptor- signaling to regulate ASM contraction. In Aim 2 will establish the mechanistic basis of
biased OGR1 signaling by assessing structure-function properties of OGR1 that dictate G protein coupling, and
the biasing function of arrestins. In Aim 3 in collaboration with Core A we will employ molecular modeling to
design new allosteric modulators to bias OGR1 signaling towards Gs/cAMP/PKA pathway activation and the
associated therapeutic benefits, using the signaling and functional assays employed in Aims 1 and 2 to guide
development and identify the most efficacious drugs. By establishing mechanisms mediating qualitative
signaling by OGR1 and developing new agents that optimally bias OGR1 and promote bronchodilation, we will
significantly advance the fields of both receptor biology and asthma therapeutics.

## Key facts

- **NIH application ID:** 10238025
- **Project number:** 5P01HL114471-08
- **Recipient organization:** RUTGERS BIOMEDICAL/HEALTH SCIENCES-RBHS
- **Principal Investigator:** RAYMOND B. PENN
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $373,143
- **Award type:** 5
- **Project period:** 2013-07-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10238025

## Citation

> US National Institutes of Health, RePORTER application 10238025, Project 4 - OGR1- and TSPO- dependent mechanisms mediated by benzodiazepines affecting ASM contraction (5P01HL114471-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10238025. Licensed CC0.

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