As many as 10% of Americans suffer chronic sleep disturbances, but the genetic mechanisms that control sleep and wake states remain largely unknown. The long-range goal of the proposed studies is to identify secreted proteins that modulate sleep, wakefulness and arousal. Zebrafish will be used as a model system because it displays clear, measurable sleep and wake behaviors and is the only vertebrate system in which such a screen is feasible. The screen will involve the generation of several hundred stably transgenic zebrafish lines that express secreted proteins under an inducible promoter. The library will be made available through the zebrafish stock center and screened for modulators of larval sleep and wakefulness. In addition, the response to mechanical, chemical, thermal and visual cues will be tested. Candidate lines will be further analyzed in secondary screens for developmental and behavioral defects. The isolated peptides will form the foundation to dissect the molecular and neural circuits of sleep. The screen will also provide candidate pathways that might be affected in human sleep disorders and that could be modulated by drugs to treat sleep disorders.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL109525-07
Application #
8692005
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Laposky, Aaron D
Project Start
2008-06-01
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Arts and Sciences
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02138
Thyme, Summer B; Schier, Alexander F (2016) Polq-Mediated End Joining Is Essential for Surviving DNA Double-Strand Breaks during Early Zebrafish Development. Cell Rep :
Santos, David P; Kiskinis, Evangelos; Eggan, Kevin et al. (2016) Comprehensive Protocols for CRISPR/Cas9-based Gene Editing in Human Pluripotent Stem Cells. Curr Protoc Stem Cell Biol 38:5B.6.1-5B.6.60
Thyme, Summer B; Akhmetova, Laila; Montague, Tessa G et al. (2016) Internal guide RNA interactions interfere with Cas9-mediated cleavage. Nat Commun 7:11750
Haesemeyer, Martin; Robson, Drew N; Li, Jennifer M et al. (2015) The structure and timescales of heat perception in larval zebrafish. Cell Syst 1:338-348
Lacoste, Alix M B; Schoppik, David; Robson, Drew N et al. (2015) A convergent and essential interneuron pathway for Mauthner-cell-mediated escapes. Curr Biol 25:1526-34
Randlett, Owen; Wee, Caroline L; Naumann, Eva A et al. (2015) Whole-brain activity mapping onto a zebrafish brain atlas. Nat Methods 12:1039-46
Haesemeyer, Martin; Schier, Alexander F (2015) The study of psychiatric disease genes and drugs in zebrafish. Curr Opin Neurobiol 30:122-30
Merkle, Florian T; Neuhausser, Werner M; Santos, David et al. (2015) Efficient CRISPR-Cas9-mediated generation of knockin human pluripotent stem cells lacking undesired mutations at the targeted locus. Cell Rep 11:875-83
Liu, Justin; Merkle, Florian T; Gandhi, Avni V et al. (2015) Evolutionarily conserved regulation of hypocretin neuron specification by Lhx9. Development 142:1113-24
Richter, Constance; Woods, Ian G; Schier, Alexander F (2014) Neuropeptidergic control of sleep and wakefulness. Annu Rev Neurosci 37:503-31

Showing the most recent 10 out of 20 publications