# Cellular/Molecular Mechanisms of Respiratory Neuronal Chemosensitivity

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2024 · $474,809

## Abstract

A discrete group of neurons located in the retrotrapezoid nucleus (RTN) that express the transcription factor,
Phox2b provide a crucial excitatory drive to regulate downstream respiratory rhythm/pattern-generating circuits. The activity of these neurons is modulated by changes in CO2 (or its proxy, H+) and various other sensory
and arousal-state inputs to control breathing; their dysfunction is implicated in various central disorders of
breathing (e.g., sudden infant death, congenital central hypoventilation syndrome (CCHS)). The molecular and
cellular mechanisms involved in CO2/H+ sensing by RTN neurons, and how those are established developmentally and adapted to pathological conditions, remain matters of continuing scrutiny. In two Aims, we address a
receptor-mediated mechanism of pH sensitivity, and explore gene expression patterns that support developmental and adaptive RTN function. In Aim 1, we use new mouse genetic models to identify mechanisms of pH sensitivity in RTN neurons that are mediated by proton-activated GPR4 modulation of a background K+ channel,
exploring the hypothesis that GPR4 is expressed in RTN neurons, where its intrinsic pH sensitivity leads to
inhibition of KNa1.1 (encoded by Kcnt1) to contribute to CO2 stimulation of breathing and arousal. We propose
to: [1.1] Test whether direct detection of protons by GPR4 accounts for its effects on RTN neuronal sensitivity
and CO2-stimulated breathing; [1.2] Test whether KNa1.1 (Slo2.2, Kcnt1) is a GPR4-inhibited K+ channel effector
in RTN neurons; and [1.3] Define sites of GPR4 protein expression. In Aim 2, we combine single cell RNA-Seq
with gene manipulation and developmental/physiological challenges to test the hypothesis that Phox2b expression dictates a distinct molecular signature that supports critical physiological functions of RTN neurons, and
that those gene expression patterns are malleable to developmental and physiological challenges in support of
breathing. We propose to: [2.1] Determine consequences of Phox2b depletion on the RTN neuron transcriptome;
[2.2] Determine effect of birth on RTN neuron transcriptome; and [2.3] Characterize developmental and adaptive gene regulation in RTN neurons. To accomplish these aims, we employ a variety of techniques at multiple
levels of analysis. Specifically, we combine genetic and viral approaches for RTN neuron-specific manipulation
of gene expression; perform electrophysiological and functional/behavioral studies at the cellular and organismal levels; and utilize molecular neuroanatomy and single neuron genetic analyses for phenotypic characterization and quantification of normal and adaptive gene expression profiles.
 Collectively, the proposed studies will provide novel information regarding molecular and cellular mechanisms
that regulate the pH-dependent activity of RTN neurons, at critical periods during development and in response
to physiological challenge, with relevance for identifying new therapeutic targets for diso...

## Key facts

- **NIH application ID:** 10756084
- **Project number:** 5R01HL108609-12
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Douglas A. Bayliss
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $474,809
- **Award type:** 5
- **Project period:** 2011-05-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10756084

## Citation

> US National Institutes of Health, RePORTER application 10756084, Cellular/Molecular Mechanisms of Respiratory Neuronal Chemosensitivity (5R01HL108609-12). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10756084. Licensed CC0.

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