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Circadian Rhythms
Biological
rhythms govern the ebb and flow
of life on planet Earth. Animals
have an internal timekeeping
mechanism that precisely
regulates 24-hour rhythms of
body function and behavior and
synchronizes them to the
day/night cycle. Circadian
pacemakers trigger behavioral
and physiological processes that
dictate our daily rhythms.
Despite the importance of the
circadian clock to all aspects
of our physiology and behavior,
the opportunity to probe the
human circadian clock only
recently became possible with
the recognition of Mendelian
circadian variants in people
(familial advanced sleep phase
syndrome, FASPS). We have now
cloned several genes and
identified mutations causing
FASPS. Study of these genes and
the proteins they encode and
engineering of the human
mutations into mouse models are
allowing study of this
fascinating phenotype and
yielding novel insights into
circadian regulation in humans.
Ultimately, such work will allow
us to understand the
similarities and differences
between the human clock and
those of model organisms. In
addition, recent studies have
also linked disruption of the
circadian clock with numerous
ailments, including cancer,
cardiovascular diseases, asthma,
and learning disorders. Thus,
studying the molecular mechanism
of human circadian rhythmicity
will have an enormous impact on
our understanding of human
health and disease. It should
also lead to new strategies for
pharmacological manipulation of
the human clock to improve the
treatment of jet lag, various
clock-related sleep and
psychiatric disorders, and other
human diseases.
(Ptacek, LJ;
Jones,
CR;
Fu,
YF.
Cold
Spring Harbor Symposium Quant
Biol.
2007;72:273-7)
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Familial
Advanced
Sleep Phase Syndrome
Familial Advanced Sleep Phase
Syndrome is a circadian rhythm disorder in which sleep onset occurs in early
evening and, as a consequence, wakefulness occurs in early morning.
Our Research
We have isolated one gene
called hPer2 that causes FASPS when it occurs in a variant (mutant)
form. Other genes that are transmitted in an autosomal dominant fashion
are known to cause FASPS in laboratory animals. We have shown that not all
families with FASPS have the hPer2 mutation. Therefore, mutations
in other genes must also be responsible for FASPS. Investigating sporadic
cases of FASPS will be valuable in identifying new mutations.
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Familial
Delayed Sleep
Phase Syndrome
FDSPS individuals experience
a delay of their sleep cycle so that they fall asleep late in the night and
wake late in the morning or afternoon. FDSPS is also thought to be
heritable, but so far very little is known about the genetic basis of FDSPS.
This sleep disorder is relatively common in adolescents and often seems to
resolve with age, but other individuals are affected by this condition all
of their lives. While it has been difficult to fully determine the
sociocultural factors that influence this sleep pattern in adolescents, it
may have a strong biological basis.
Our Research
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Familial
Natural Short Sleepers
Familial Natural Short Sleepers have a behavioral trait in which they have a lifelong tendency to sleep only 4 – 6 hours per night. These individuals awaken refreshed and energetic and experience this short sleep pattern even when they are on vacation and relatively free of obligations.
Our Research
We have identified a mutation in a transcriptional repressor (hDEC2-P384R) that is associated with a human short sleep phenotype. Activity profiles and sleep recordings of transgenic mice carrying this mutation showed increased vigilance time and less sleep time than control mice in a zeitgeber time and sleep deprivation-dependent manner. These mice represent a model of human sleep homeostasis that provides an opportunity to probe the effect of sleep on human physical and mental health.
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Advanced
Sleep Phase syndrome of Aging
Advanced Sleep Phase of
Aging is a profound problem for the elderly population. In fact, one
third of the population over 65 years of age experience a change in their
sleep cycle when they fall asleep at earlier and earlier times and then wake
up early in the morning. The cause of this condition is not known but it
appears in association with the normal aging process. We hypothesize that
age-related changes in gene expression (rather than gene mutations) are one
possible cause of the shortened sleep time for the elderly.
Our Research
We're
currently testing the hypothesis that transcriptional
repression of a gene (hPer2) as a stochastic process
with aging causes the phenotype of earlier sleep wake
times in humans.
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Participate in a Research Study
We are
currently enrolling participants affected by FASPS, FDSPS, and FNSS into our circadian studies.
As an initial screening
process, you will be asked to fill out a set of questionnaires. These
questionnaires are used to help our clinical sleep doctor assess your sleep
patterns and account for factors affecting the quality of your sleep.
Once you return the questionnaire and your
eligibility is confirmed, a short sleep interview over the phone will be scheduled to find out more about your sleeping patterns. Participants will
then sign consent forms detailing the study objectives, UCSF health privacy
policy, and procedures and donate either a blood or saliva sample for DNA
extraction. We may also request clinical files or other medical
records.
We would
truly appreciate hearing from you if you feel you have FASPS, FDSPS, or FNSS and are interested in participating in
our studies.
Please
refer to our
Contact Page for more
instructions.
We are currently not
enrolling participants affected by ASPS of Aging. We may
open enrollment in the future. If you would like to be
contacted in the future for our circadian studies,
please contact our clinical coordinators with your
information. Please refer to the
Contact Page for more
information.
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Publications
1.
Modeling of a Human Circadian
Mutation Yields Insights into
Clock Regulation by PER2;
Cell 128, 59-70, January
12, 2007
2.
Familial advanced sleep-phase
syndrome: A short-period circadian
rhythm variant in humans; Nature Medicine, Vol 5, No 9, 1062-65, September 1999
3.
Functional consequences of a
CKIδ mutation causing familial advanced
sleep phase syndrome;
Nature, Vol 434, 640-44,
31 March 2005
4.
An hPer2 Phosphorylation Site
Mutation in Familial Advanced Sleep Phase Syndrome;
Science, Vol 291, 1040-43,
9 February 2001
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