# GABAA Receptor-Mediated Modulation of Lung Inflammation

> **NIH NIH K08** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $166,212

## Abstract

Project Summary/Abstract
There is significant evidence that anesthetics which act at the GABAA receptor alter immune function and that
multiple immune cell types express functional GABAA receptors. However, the mechanism of this immune
modulation is unknown. In this proposal, we present exciting preliminary data demonstrating that mice lacking
expression of the GABAA receptor α4 subunit (gabra4), a subunit expressed in immune cells including CD4+
lymphocytes, have significantly greater lung inflammation after sensitization with house dust mite antigen, a
common allergic asthma model. This heightened inflammation results in greater in vivo airway reactivity. We
also demonstrate that gabra4 knockout CD4+ cells express increased inflammatory cytokines compared to wild
type CD4+ cells when stimulated via the T cell receptor in vitro, suggesting the hyper-inflammatory phenotype of
the gabra4 knockout mouse may be CD4+ cell-mediated. We hypothesize that GABAA receptor currents, which
are depolarizing in CD4+ cells, alter calcium signaling processes key in lymphocyte activation and function,
specifically calcium oscillations and store-operated calcium entry. We propose to demonstrate that α4 subunit
containing-GABAA receptors mediate currents in CD4+ cells which are augmented by GABAA receptor ligands,
including XHE-III-74A, a novel α4 subunit selective positive allosteric modulator developed by a collaborator.
We will also determine if the CD4+ cell is key in producing the gabra4 KO mouse’s hyper-inflammatory phenotype
by performing adoptive T cell transfer experiments. Furthermore, we propose to determine if altered GABAAR
signaling affects CD4+ cell calcium dynamics (oscillations and store operated calcium entry) using a novel in situ
calcium imaging technique that utilizes precision-cut lung slice technology. This offers the key advantage of
maintaining the native environment of the inflamed lung. Finally, we will determine if XHE-III-74A, an α4 subunit-
selective GABAA receptor activator that does not cross the blood brain barrier, will limit house dust mite antigen
induced lung inflammation and airway hyper-responsiveness when administered chronically during the
sensitization process. Although the studies proposed here focus on lung inflammation, the implications of this
work may be relevant to inflammatory processes of many types. Given the widespread use of GABAergic
medications, this research promises to be of high clinical significance. My department and Columbia University
provide an ideal environment to complete these studies, as all necessary support is already in place. In addition,
my proven mentoring committee provides a perfect blend of skills to help guide the science, including expertise
in ion channel physiology, lung biology, immunology, and calcium signaling. A comprehensive career
development plan has been established, including coursework and additional training. Taken as a whole, this
K08 proposal outlines a robust pathway to sc...

## Key facts

- **NIH application ID:** 9843724
- **Project number:** 5K08HL140102-03
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Gene Thomas Yocum
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $166,212
- **Award type:** 5
- **Project period:** 2018-01-09 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9843724

## Citation

> US National Institutes of Health, RePORTER application 9843724, GABAA Receptor-Mediated Modulation of Lung Inflammation (5K08HL140102-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9843724. Licensed CC0.

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