Background
Neuroscience stands at the forefront of biology in the
exploration of some of the most profound questions concerning
living systems. The understanding of how nervous systems
function and how they generate integrative behavior and
cognition remain one of the most difficult challenges in
science today. Currently, neuroscience is entering yet another
era with the genomics and genetics revolution. The integration
of neuroscience and genomics (“neurogenomics”),
the use of molecular genetics to manipulate the mouse genome,
and the use of novel molecular tools to define neural circuits
are revolutionizing our ability to discover, define and
decode the neural and genetic bases of behavior. The convergence
of neuroscience and genetics has had a profound impact on
the circadian field. This stems from two fundamental discoveries
in the field: the localization of circadian pacemakers in
the nervous systems of animals (e.g., the discovery of the
suprachiasmatic nucleus (SCN) as the dominant pacemaker
in mammals; and the isolation of circadian mutants and the
subsequent cloning of circadian clock genes (e.g., the period
locus in Drosophila and the Clock locus in mammals).
Circadian clocks have been described in organisms ranging
from bacteria to humans and control numerous aspects of
behavior, physiology, and biochemistry, including such things
as sleep/wake cycles, locomotor activity, hormone synthesis,
and visual sensitivity. These clocks are important for the
normal homeostasis of the organism and disruption of these
processes can contribute to human disorders. The last decade
has witnessed a revolution in our understanding of the molecular
mechanism of circadian clocks in animals, including the
identification of at least seven different genes that are
essential elements of the circadian clock mechanism (Clock,
Bmal1, Per1, Per2, Cryptochrome1, Cryptochrome2 and
Casein kinase 1 epsilon). With the initial discovery
of these clock genes came the realization and documentation
that the capacity for circadian expression is widespread
throughout the body. Most peripheral organs and tissues
can express circadian oscillations in isolation, yet still
receive and may require input from the dominant circadian
pacemaker in the suprachiasmatic nucleus (SCN) in vivo.
The existence of both central and peripheral circadian oscillators
raises a number of novel questions and hypotheses concerning
the integration of the system to control the behavioral
state of the organism.
Mission
Investigate how the multioscillatory circadian system of
mammals can be regulated and entrained at the level of central
and peripheral oscillators.
Strategy
- Test the hypothesis that central and peripheral oscillators
both contribute to the normal physiological function and
integration of the circadian system to regulate behavioral
state. Tissue-specific, conditional regulation of circadian
clock gene function in central vs. peripheral tissues
will be used to test the role of these components in generating
and entraining circadian behavior.
- Test the hypothesis that chemical and genetic tools
can be used to manipulate the period and phase of circadian
rhythms in mammals in a manner that is more efficacious
than current methods which are based primarily on the
use of environmental light manipulation, melatonin and
nonphotic inputs. Specifically we will test the hypothesis
that small molecules can reset circadian rhythms in mammals
more efficiently than light cycles because these molecules
should have direct access to both central and peripheral
oscillators, whereas, light cycles can only access the
circadian system via the retina and suprachiasmatic nucleus.
- Test the mechanism of action of chemical and genetic
tools discovered in Strategy 2 by assessing their molecular
targets and validating these agents at the cellular and
organismal level. Human genetic variants in circadian
clock gene targets will also be used to evaluate the efficacy
and specificity of these tools in mouse models of these
human disorders.
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