# Project 2

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

## Abstract

Project Summary/Abstract – Project 2
 In people with obstructive sleep apnea (OSA), airflow obstruction results in hypercarbia and other signals
that increase ventilation, dilate the airway, and also trigger cortical arousals from sleep. Current therapies such
as CPAP focus on airway opening, but compliance with these therapies is poor, and many patients continue to
have daytime sleepiness. As recurrent arousals from sleep contribute to daytime sleepiness and other
consequences of OSA, new methods that maintain sleep in OSA without disrupting ventilation would address
an important, unmet need in OSA treatment.
 In the last cycle of this P01, Dr. Saper’s group (Project 1) showed that calcitonin gene-related peptide
(CGRP) neurons of the lateral parabrachial nucleus are necessary for cortical arousals in response to
hypercapnia. Specifically, inactivation of PBCGRP neurons substantially delays or eliminates cortical arousals in
response to hypercapnia without blunting ventilatory responses. Thus, the PBCGRP neurons are essential for
driving cortical arousals, but they are not necessary for ventilatory responses to hypercapnia. We hypothesize
that activation of inhibitory inputs to the PBCGRP neurons will delay or eliminate cortical arousals to hypercapnia
without altering ventilatory responses.
 Our Aims seek to identify these inputs and their receptors on the PBCGRP neurons, with the ultimate goal of
selectively reducing activity in the PBCGRP neurons to prevent cortical arousals while preserving ventilatory
responses. This Project synergizes well with Projects 1, 3, and 4 that seek to enhance ventilatory responses to
hypercapnia in mice, and Project 5 which seeks to identify pharmacological methods to improve OSA in
people. We will first use conditional and conventional tracing methods to identify afferents to the PBCGRP
neurons, and then we will use Channelrhodopsin-assisted circuit mapping (CRACM) to establish synaptic
connectivity. Using single cell sequencing techniques, we will then identify receptors expressed by the PBCGRP
neurons, and confirm receptor expression using in situ hybridization and in vitro calcium imaging. We will then
use fos and fiber photometry to determine which afferent pathways to the PBCGRP neurons are sleep-active.
Last, we will determine whether signaling through inhibitory inputs to the PBCGRP neurons delays or eliminates
cortical arousals triggered by brief period of hypercapnia. We will measure the latency to cortical arousal after
hypercapnia in combination with photostimulation of inhibitory inputs to the PBCGRP neurons and then with
pharmacological inhibition of the PBCGRP neurons.
 Collectively, these multidisciplinary experiments will identify crucial anatomical and neurochemical inputs to
the PBCGRP neurons that should provide new pharmacological opportunities for maintaining sleep in OSA
without inhibiting airway opening.

## Key facts

- **NIH application ID:** 9854433
- **Project number:** 1P01HL149630-01
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** THOMAS E SCAMMELL
- **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/9854433

## Citation

> US National Institutes of Health, RePORTER application 9854433, Project 2 (1P01HL149630-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9854433. Licensed CC0.

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