# Molecular and Cellular Mechanisms Underlying the Circadian Timing of Sleep

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $472,539

## Abstract

Project Summary
Sleep is regulated by a circadian process that modulates the timing of sleep and a homeostatic process that
adjusts the amount and depth of sleep in response to sleep need. Studies over the past few decades have
delineated many of the molecular mechanisms underlying the core circadian clock. However, the mechanisms
by which this core clock regulates sleep remain poorly understood. Recently, using Drosophila as a gene
discovery system, we identified a novel molecule named WIDE AWAKE (WAKE) that mediates the circadian
timing of sleep onset. WAKE is expressed in arousal-promoting clock neurons and upregulates GABA
signaling in a time-dependent manner to promote sleep in Drosophila. Strikingly, we find a single homolog of
WAKE in mice (mWAKE) and have determined that mWAKE is specifically enriched in the suprachiasmatic
nucleus (SCN), the master circadian pacemaker in mammals. The overall goal of this proposal is to
characterize the molecular and cellular mechanisms underlying the circadian timing of sleep, by investigating
the function of mWAKE in mice. To do this, we will employ an array of approaches, including molecular,
biochemical, genetic, electrophysiological, and behavioral studies. Specifically, we propose to 1) determine the
molecular mechanisms underlying mWAKE function in cultured cells and SCN slices, 2) examine the sleep and
circadian phenotypes of mice genetically lacking mWAKE, and 3) characterize and identify the function of
specific mWAKE circuits in mice. These studies will be carried out with an outstanding collaborative team, with
expertise in mouse genetics, large-scale in situ hybridization experiments, SCN slice physiology, and
circadian/sleep behavioral analyses and should yield new insights into SCN function and the molecular and
cellular pathways mediating the timing of sleep. ~15 million Americans have to work alternate shift schedules,
and emerging evidence suggests that dysregulated sleep/wake cycles in humans can have significant adverse
health consequences. Thus, there is an increased urgency to understand the circadian timing mechanisms
underlying sleep. The proposed studies should lead to a better understanding of these mechanisms and thus
may facilitate the potential development of novel therapeutic targets for the treatment of circadian sleep/wake
desynchrony.

## Key facts

- **NIH application ID:** 9858434
- **Project number:** 5R01NS094571-05
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Mark N Wu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $472,539
- **Award type:** 5
- **Project period:** 2016-05-15 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9858434

## Citation

> US National Institutes of Health, RePORTER application 9858434, Molecular and Cellular Mechanisms Underlying the Circadian Timing of Sleep (5R01NS094571-05). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9858434. Licensed CC0.

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