Sleep disorders and environmental challenges that reduce daily sleep amount act upon systems that drive the daily reciprocal relationship between sleep and wakefulness. Unfortunately, the physiological, neural, and genetic composition of these systems remains largely undetermined. The identification of the genes and molecules that drive and respond to changes in daily sleep-wake amount will provide new therapeutic targets for the treament of sleep disorders and co-morbid disease states. Since the reciprocal relationship between sleep and wakefulness is driven by 1) the circadian timing system and 2) a homeostatic system that allots sleep amount as a function of prior wake duration, it stands to reason that the two systems share common molecular elements. The experiments described in this proposal will take advantage of recently generated lines of conditional transgenic mice to test the hypothesis that Bmall, a core component of the circadian timing system, facilitates wakefulness and bolsters the homeostatic response to sleep loss.
Specific aim 1 will determine whether amplication of Bmall expression enhances wakefulness or modifies the homeostatic response to sleep loss by polysomnographically analyzing sleep-wake states in a transgenic mouse line that over-expresses Bmall but conserves circadian function.
Specific aim 2 will determine where the influences of Bmall on the sleep-wake cycle are mediated by examining sleep-wake states in transgenic mouse lines that exclusively express Bmall in the brain or periphery.
Specific aim 3 will determine whether influences of Bmall on sleep-wake states are driven directly or induced through developmental influences of the mutation. This will be accomplished by examining sleep-wake states in transgenic mice whose expression of Bmall in brain tissue will be conditionally activated and deactivated by doxycycline administration. The goal of these studies is to establish and characterize a molecular link between the circadian timing system and the processes that drive sleep and/or wakefulness. Through the use of new trangenic technology this study will allow the analysis of sleep during the temporal and spatial manipulation of gene expression to examine potential therapeutic targets for treatment of sleep disroders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54NS060659-05
Application #
8377067
Study Section
Special Emphasis Panel (ZNS1-SRB-R)
Project Start
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$290,453
Indirect Cost
$72,455
Name
Morehouse School of Medicine
Department
Type
DUNS #
102005451
City
Atlanta
State
GA
Country
United States
Zip Code
30310
Azzi, Abdelhalim; Evans, Jennifer A; Leise, Tanya et al. (2017) Network Dynamics Mediate Circadian Clock Plasticity. Neuron 93:441-450
Ehlen, J Christopher; Brager, Allison J; Baggs, Julie et al. (2017) Bmal1 function in skeletal muscle regulates sleep. Elife 6:
Reynolds, James P; Jimenez-Mateos, Eva M; Cao, Li et al. (2017) Proteomic Analysis After Status Epilepticus Identifies UCHL1 as Protective Against Hippocampal Injury. Neurochem Res 42:2033-2054
Simmons, Lauren J; Surles-Zeigler, Monique C; Li, Yonggang et al. (2016) Regulation of inflammatory responses by neuregulin-1 in brain ischemia and microglial cells in vitro involves the NF-kappa B pathway. J Neuroinflammation 13:237
White, Todd E; Surles-Zeigler, Monique C; Ford, Gregory D et al. (2016) Bilateral gene interaction hierarchy analysis of the cell death gene response emphasizes the significance of cell cycle genes following unilateral traumatic brain injury. BMC Genomics 17:130
Reynolds, James P; Miller-Delaney, Suzanne F C; Jimenez-Mateos, Eva M et al. (2015) Transcriptional Response of Polycomb Group Genes to Status Epilepticus in Mice is Modified by Prior Exposure to Epileptic Preconditioning. Front Neurol 6:46
Evans, Jennifer A; Suen, Ting-Chung; Callif, Ben L et al. (2015) Shell neurons of the master circadian clock coordinate the phase of tissue clocks throughout the brain and body. BMC Biol 13:43
Rahman, Shadab A; Castanon-Cervantes, Oscar; Scheer, Frank A J L et al. (2015) Endogenous circadian regulation of pro-inflammatory cytokines and chemokines in the presence of bacterial lipopolysaccharide in humans. Brain Behav Immun 47:4-13
Evans, Jennifer A; Leise, Tanya L; Castanon-Cervantes, Oscar et al. (2015) Neural correlates of individual differences in circadian behaviour. Proc Biol Sci 282:
Meller, Robert; Pearson, Andrea; Simon, Roger P (2015) Dynamic changes in DNA methylation in ischemic tolerance. Front Neurol 6:102

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