Paul- Project 1 Program Director/Principal Investigator (Last, First, Middle): MacLeish, Peter R. PROJECT SUMMARY (See instructions): In today's demanding 24-hour society the prevalence of sleep disorders continues to increase;however, the development of effective treatments for those disorders has not kept pace. One of the primary reasons is that many of the genetic and molecular pathways that underlie basic sleep processes are still undefined. Forward genetics approaches have yielded novel therapeutic targets and more effective treatments for a variety of diseases;however, similar milestones in the study of sleep disorders have been elusive. It has become apparent in the last several years that the genetics of sleep are complex, involving multiple genes and gene interactions with potentially small effect sizes. Larger-scale genomic approaches are likely to provide the necessary power uncover the genes that underlie sleep processes. In this application we propose a forward genetics approach that takes advantage of natural variation occurring in inbred mice. We have characterized 53 sleep-wake phenotypes in 14 inbred mouse strains in sleep-replete and sleep-deprived conditions. We propose to expand this dataset to add a minimum of 11 additional strains to provide sufficient statistical power for quantitative trait loci (QTL) analysis and positional cloning in subsequent recombinant hybrid crosses to transition from QTL to gene. This endeavor will combine a well-established paradigm of comparative phenotyping of a genetically tractable animal model with powerful genetic mapping tools to identify novel sleep regulatory genes. Consequently, these experiments will not only identify new sleep genes, they will also help verify and clarify previously mapped genes whose roles are not yet clearly defined. Ancillary benefits of this proposal include the potential identification of practical biomarkers of sleepiness, which is often cited as one of the most pressing needs in contemporary sleep research.

Public Health Relevance

Sleep disorders can be debilitating, are often co-morbid with somatic diseases, and are often predictive of mental illness. This project seeks to identify potential targets to improve the treatment of sleep disorders by using a phenomics approach to discover new sleep regulatory genes and to identify sleep regulatory properties of known genes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
1U54NS083932-01
Application #
8585152
Study Section
Special Emphasis Panel (ZNS1-SRB-N (03))
Project Start
Project End
2018-06-30
Budget Start
2013-08-15
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$153,292
Indirect Cost
$44,958
Name
Morehouse School of Medicine
Department
Type
DUNS #
102005451
City
Atlanta
State
GA
Country
United States
Zip Code
30310
Wu, Junjun; Leng, Tiandong; Jing, Lan et al. (2016) Two di-leucine motifs regulate trafficking and function of mouse ASIC2a. Mol Brain 9:9
Gianesini, Coralie; Hiragaki, Susumu; Laurent, Virginie et al. (2016) Cone Viability Is Affected by Disruption of Melatonin Receptors Signaling. Invest Ophthalmol Vis Sci 57:94-104
Vann, Kiara T; Xiong, Zhi-Gang (2016) Optogenetics for neurodegenerative diseases. Int J Physiol Pathophysiol Pharmacol 8:1-8
Leng, Tian-Dong; Si, Hong-Fang; Li, Jun et al. (2016) Amiloride Analogs as ASIC1a Inhibitors. CNS Neurosci Ther 22:468-76
Jiang, Nan; Wu, Junjun; Leng, Tiandong et al. (2016) Region specific contribution of ASIC2 to acidosis-and ischemia-induced neuronal injury. J Cereb Blood Flow Metab :
Jockers, Ralf; Delagrange, Philippe; Dubocovich, Margarita L et al. (2016) Update on melatonin receptors: IUPHAR Review 20. Br J Pharmacol 173:2702-25
Jones, Kelly A; Han, Ji Eun; DeBruyne, Jason P et al. (2016) Persistent neuronal Ube3a expression in the suprachiasmatic nucleus of Angelman syndrome model mice. Sci Rep 6:28238
Inoue, Koichi; Leng, Tiandong; Yang, Tao et al. (2016) Role of serum- and glucocorticoid-inducible kinases in stroke. J Neurochem 138:354-61
Meller, Robert; Pearson, Andrea; Simon, Roger P (2015) Dynamic changes in DNA methylation in ischemic tolerance. Front Neurol 6:102
Zeng, Zhao; Inoue, Koichi; Sun, Huawei et al. (2015) TRPM7 regulates vascular endothelial cell adhesion and tube formation. Am J Physiol Cell Physiol 308:C308-18

Showing the most recent 10 out of 31 publications