Virtually all eukaryotic organisms appropriately examined have been shown to possess the capacity for endogenous temporal control and organization known as a circadian rhythm. The cellular machinery responsible for generating rhythms is collectively known as the biological clock. A healthy circadian clock underlies both physical and mental health. Because of the ubiquity of its influence on human mental and physiological processes - from circadian changes in basic human physiology to the clear involvement of rhythms in work/rest cycles and sleep - understanding the clock is basic to prevention and treatment of many physical and mental illnesses.
Our specific aims are designed to further our understanding of the means through which the clock regulates cell behavior, including cell growth and in some cases cancer.
Specific Aim #1 builds upon our identification of the cell cycle regulator checkpoint kinase 2 as a conditional modifier of clock function in Neurospora. We will pursue this work in mammalian cells in culture and in mice to probe the interconnectedness of the circadian system and cell cycle.
Specific Aim #2 builds upon our ongoing analysis of non-circadian output oscillators in Neurospora as an important means of mediating circadian output. We will identify components of output oscillators and determine the means through which they are connected to the circadian cycle.
Specific Aim #3 builds upon our strong grounding in genomics. We will carry out an overexpression screen and a knockout screen for components of output oscillators and will use microarrays to identify the clock-controlled and output oscillator-controlled genes in Neurospora. Our long term goals are to describe, in the language of genetics and biochemistry, the feedback cycle comprising the circadian clock, how this cycle is synchronized with the environment, and how time information generated by the feedback cycle is used to regulate the behavior of cells and organisms. These projects are complementary and mutually enriching in that they rely on genetic and molecular techniques to dissect, and ultimately to understand, the organization of the cell as a function of time.

Public Health Relevance

Virtually all eukaryotic organisms appropriately examined have been shown to possess the capacity for endogenous temporal control and organization known as a circadian rhythm, the output of a biological clock. A healthy circadian clock underlies both physical and mental health. Because of the ubiquity of its influence on human mental and physiological processes - from circadian changes in basic human physiology to the clear involvement of rhythms in work/rest cycles and sleep - understanding the clock is basic to prevention and treatment of many physical and mental illnesses.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM083336-22
Application #
8025944
Study Section
Special Emphasis Panel (ZRG1-NCF-D (09))
Program Officer
Tompkins, Laurie
Project Start
1989-09-01
Project End
2012-03-18
Budget Start
2011-01-01
Budget End
2012-03-18
Support Year
22
Fiscal Year
2011
Total Cost
$724,376
Indirect Cost
Name
Dartmouth College
Department
Genetics
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Dasgupta, Arko; Fuller, Kevin K; Dunlap, Jay C et al. (2016) Seeing the world differently: variability in the photosensory mechanisms of two model fungi. Environ Microbiol 18:5-20
Wang, Bin; Zhou, Xiaoying; Loros, Jennifer J et al. (2016) Alternative Use of DNA Binding Domains by the Neurospora White Collar Complex Dictates Circadian Regulation and Light Responses. Mol Cell Biol 36:781-93
Wang, Zheng; Li, Ning; Li, Jigang et al. (2016) The Fast-Evolving phy-2 Gene Modulates Sexual Development in Response to Light in the Model Fungus Neurospora crassa. MBio 7:e02148
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Hurley, Jennifer M; Loros, Jennifer J; Dunlap, Jay C (2016) The circadian system as an organizer of metabolism. Fungal Genet Biol 90:39-43
Hurley, Jennifer; Loros, Jennifer J; Dunlap, Jay C (2015) Dissecting the mechanisms of the clock in Neurospora. Methods Enzymol 551:29-52
Oliveira, Anderson G; Stevani, Cassius V; Waldenmaier, Hans E et al. (2015) Circadian control sheds light on fungal bioluminescence. Curr Biol 25:964-8
Emerson, Jillian M; Bartholomai, Bradley M; Ringelberg, Carol S et al. (2015) period-1 encodes an ATP-dependent RNA helicase that influences nutritional compensation of the Neurospora circadian clock. Proc Natl Acad Sci U S A 112:15707-12
Fuller, Kevin K; Loros, Jennifer J; Dunlap, Jay C (2015) Fungal photobiology: visible light as a signal for stress, space and time. Curr Genet 61:275-88
Fuller, Kevin K; Chen, Shan; Loros, Jennifer J et al. (2015) Development of the CRISPR/Cas9 System for Targeted Gene Disruption in Aspergillus fumigatus. Eukaryot Cell 14:1073-80

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