# Project 3

> **NIH NIH P01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $438,301

## Abstract

Project Summary/ Abstract- Project 3
Obstructive sleep apnea (OSA) is a highly prevalent breathing disorder characterized by recurrent episodes of
partial and complete airway obstructions that occur exclusively during sleep. OSA poses a significant public
health burden due to its being associated with the development of adverse cardiovascular, cognitive, and
endocrine conditions. With high relevance to the current proposal, reestablishment of airway patency following
an obstructive event is often associated with arousal from sleep (defined by activation of the EEG), resulting in
sleep fragmentation, reduced sleep time, and excessive daytime sleepiness in many cases. This disruption of
sleep continuity is thought to underlie many of the pathological consequences of OSA. Numerous failed
attempts to treat OSA pharmacologically by enhancing ventilatory drive have been limited by unwanted
increases in arousability that accompany ventilatory augmentation. Hence, development of methods to
enhance ventilatory responses without driving cortical arousal in response to hypercapnia would be a major
advance with translational impact for OSA. The detailed circuits underling respiratory versus cortical arousals
in response to hypercapnia — including key cell groups, their targets and their transmitters — remains,
however, incompletely understood. This knowledge gap has hampered the development of pharmacological
strategies to treat OSA. The objective in this particular application is to demonstrate a role for CO2-responsive,
glutamatergic FoxP2 neurons of the lateral crescent parabrachial nucleus (PBclFoxP2) in driving ventilation
independent of arousal. The central hypothesis is that activation of select forebrain inputs to the PBclFoxP2
neurons will enhance the ventilatory response to hypercapnia without driving cortical arousals. The rationale
for the proposed research is that successful demarcation of cortical versus respiratory arousal components of
hypercapnia circuitry would enable pharmacological treatment strategies for OSA that derive their clinical
benefit from the dissociation of the respiratory and arousal responses to hypercapnia. Guided by strong
preliminary data, our hypotheses will be tested by pursuing four specific aims: 1) Identify and map presynaptic
forebrain inputs to PBclFoxP2 neurons; 2) through transcriptome analysis, uncover unique and “druggable”
receptors on CO2-responsive vlPB cells, including the PBclFoxP2 cell population; 3) define the state-dependent
activity of presynaptic forebrain inputs to PBcl neurons; and 4) determine whether signaling from delimited,
neurochemically-defined forebrain inputs can augment the ventilatory response to hypercarbia. The approach
is intellectually and technically innovative because of its emphasis on forebrain inputs to PBclFoxP2 neurons in
the context of ventilatory control, and because it employs a novel combination of newly developed and
validated technical approaches. This work is significant...

## Key facts

- **NIH application ID:** 9854434
- **Project number:** 1P01HL149630-01
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Patrick M Fuller
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $438,301
- **Award type:** 1
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9854434

## Citation

> US National Institutes of Health, RePORTER application 9854434, Project 3 (1P01HL149630-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9854434. Licensed CC0.

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