CLOCK MECHANISM UNDERLYING DROSOPHILA RHYTHMIC BEHAVIOR

  • Edery, Isaac (PI)
  • EDERY, ISAAC (PI)
  • EDERY, ISAAC (PI)
  • EDERY, ISAAC (PI)

Project Details

Description

Daily fluctuations in complex behavior is influenced by the rhythmicity
of endogenous circadian (approximately 24 hr) clocks that respond to
external time cues. Malfunctions in the human circadian timing system
are implicated in the manifestation of several disease states, including
manic-depression and seasonal affective disorders. A better
understanding of the time-keeping mechanism should lead to the
development of more efficient treatments to combat disorders associated
with altered clock function. Studies in different model systems have
greatly contributed to our knowledge of the basic properties that govern
human circadian rhythms. Collectively, studies on a variety of organisms
suggest that similar macromolecular pathways are required for the proper
functioning of clocks. Despite these important findings, in no case is
the time-keeping mechanism known. A significant limitation is the lack
of identified clock components. Recent evidence indicates that the
Drosophila period (per) protein (PER) is a bona fide "gear" in a
circadian clock. The main focus of this proposal is to elucidate how PER
activity contributes to the mechanism that measures or tells time.

The experimental strategy is based on our recent studies demonstrating
that PER is (i) progressively phosphorylated through a circadian cycle
and (ii) contains a novel dimerization motif termed PAS common to several
transcription factors. First, the levels of the different isoforms of
PER will be precisely measured as a function of time. Furthermore, the
relationship between PER phosphorylation and dimerization will be
investigated. These studies will also include a collaborative effort to
investigate the components that interact with PER in wild type flies and
in the recently identified arrhythmic mutant timeless. Second, the
phosphorylated status of PER will be determined after perturbing the
phase of the clock. In related studies, we will explore the hypothesis
that temperature influences the dynamics of PER oligomerization. Third,
phosphorylation sites on PER and kinases that phosphorylate PER will be
identified. Site-directed mutagenesis of these sites should result in
animals with altered behavioral rhythms. It is anticipated that
elucidation of the biochemical activities that underlie Drosophila
circadian clocks will provide a better framework for understanding and
manipulating human clocks.
StatusFinished
Effective start/end date7/1/951/31/18

Funding

  • National Institute of Neurological Disorders and Stroke: $45,000.00
  • National Institute of Neurological Disorders and Stroke: $350,565.00
  • National Institute of Neurological Disorders and Stroke: $339,063.00
  • National Institute of Neurological Disorders and Stroke: $345,911.00
  • National Institute of Neurological Disorders and Stroke: $329,302.00
  • National Institute of Neurological Disorders and Stroke: $350,294.00
  • National Institute of Neurological Disorders and Stroke: $339,063.00
  • National Institute of Neurological Disorders and Stroke: $332,934.00
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke: $338,517.00
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke: $335,673.00
  • National Institute of Neurological Disorders and Stroke: $327,196.00
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke: $85,250.00
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke: $325,818.00
  • National Institute of Neurological Disorders and Stroke: $341,789.00
  • National Institute of Neurological Disorders and Stroke: $335,840.00
  • National Institute of Neurological Disorders and Stroke: $331,605.00
  • National Institute of Neurological Disorders and Stroke: $332,783.00
  • National Institute of Neurological Disorders and Stroke: $326,056.00
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke: $15,500.00

ASJC

  • Medicine(all)
  • Neuroscience(all)
  • Genetics
  • Biochemistry, Genetics and Molecular Biology(all)
  • Molecular Biology
  • Geometry and Topology
  • Biochemistry
  • Cancer Research

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