Emerging data point to an important role for sleep in human health. Despite its importance, the function of sleep remains one of neurobiology's great mysteries. Our ability to gain fundamental insights into the function of sleep as well as potentially identify novel targets for the diagnosis and treatment of sleep disorders is hindered by our lack of understanding of the molecular genetic mechanisms underlying sleep. To identify novel genes required for sleep regulation, Dr. Wu, the principal investigator, has carried out a forward genetic screen in Drosophila. By screening approximately 3,000 mutant lines, he has identified 10 short-sleeping mutant strains. One of these mutants carries a novel mutation in a dopamine transporter known to regulate sleep, a finding which validates this approach. The goal of this proposal is to identify the gene mutated in one of the shortest sleepers, named catnap, and to determine the behavioral and signaling mechanisms underlying its phenotype. Catnap mutants have severely reduced and fragmented baseline sleep. Mapping experiments localize the catnap gene to an approximately 600 kb interval.
In Aim 1, he will test the hypothesis that the short-sleeping phenotype seen in catnap is caused by changes in arousal threshold or sleep homeostasis. Because the phenotype of catnap mutants resembles that seen with manipulation of cAMP signaling, in Aim 2, he will test the hypothesis that catnap acts via cAMP signaling to regulate sleep.
In Aim 3, he will clone the gene mutated in catnap, to identify a novel molecular component required for sleep regulation. These studies will be carried out in the laboratory of Dr. Amita Sehgal, a pioneer in circadian and sleep research. The training environment provided by the Division of Sleep Medicine at the University of Pennsylvania, led by Dr. Allan Pack, is ideal for the development of academic sleep physicians. This training grant will provide an excellent vehicle for Dr. Wu to learn about the design, execution, and analysis of behavioral experiments and facilitate his transition towards an independent career as a physician-scientist studying the molecular mechanisms underlying sleep. Lay Description: Our ability to design new diagnostic tools and treatments for disorders of sleep is impaired by our lack of understanding of the molecular mechanisms underlying sleep. To identify molecules important for sleep regulation, this proposal will characterize a novel short-sleeping fly mutant.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS059671-06
Application #
8265902
Study Section
NST-2 Subcommittee (NST)
Program Officer
Mitler, Merrill
Project Start
2008-04-01
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
6
Fiscal Year
2012
Total Cost
$172,881
Indirect Cost
$12,806
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Liu, Sha; Lamaze, Angelique; Liu, Qili et al. (2014) WIDE AWAKE mediates the circadian timing of sleep onset. Neuron 82:151-66
Raizen, David M; Wu, Mark N (2011) Genome-wide association studies of sleep disorders. Chest 139:446-52
Wu, Mark N; Joiner, William J; Dean, Terry et al. (2010) SLEEPLESS, a Ly-6/neurotoxin family member, regulates the levels, localization and activity of Shaker. Nat Neurosci 13:69-75
Wu, Mark N; Ho, Karen; Crocker, Amanda et al. (2009) The effects of caffeine on sleep in Drosophila require PKA activity, but not the adenosine receptor. J Neurosci 29:11029-37
Zheng, Xiangzhong; Koh, Kyunghee; Sowcik, Mallory et al. (2009) An isoform-specific mutant reveals a role of PDP1 epsilon in the circadian oscillator. J Neurosci 29:10920-7