Circadian Clock

Researchers Find Key to Circadian Clock

United Press International June 28, 2001

PHILADELPHIA, Jun 28, 2001 (United Press International via COMTEX) -- Scientists at the University of Pennsylvania School of Medicine have discovered a key to the body's circadian clock that might help explain why people have heart attacks more often in the mornings and why some cancer medications are more effective at different times of the day.

Their discovery, to be published in this Friday's edition of the journal Cell, provides the first evidence of how hormones and vitamins can reset a circadian clock and details how activation of vitamin A receptors can regulate the rhythm of the clock. This gives researchers an important clue as to how the "master clock," which lies deep in the brain, regulates organs like the liver, kidneys and blood vessels by controlling circadian clocks within them. "It might even apply to cells," study co-author Peter McNamara told United Press International.

"Until recently it was thought we just had a central clock in the brain that controlled the body's various circadian rhythms, such as those in the sleep-wake cycle, metabolic, hormonal and cardiovascular systems. We've found blood vessels contain their own peripheral circadian system, similar to those in other organs."

The findings could lead to new treatments based on the body's timing mechanisms or even methods for resetting the body's clock to overcome jet lag or intermittent shift work, the lead author, Dr. Garret FitzGerald, told UPI. FitzGerald, chairman of Penn's Department of Pharmacology, said altered biorhythms have clinical consequences.

Heart attacks and strokes occur most commonly early in the morning when blood pressure is at its highest point, he explained. "Our findings also link hormonal and vitamin control for the first time to the circadian rhythms that control body temperature, sleep and wakefulness, pain sensitivity and the response to drugs," FitzGerald said.

He said it is known the response to certain drugs used in the treatment of cancer vary substantially depending on the time of day that they are administered "But this work also elucidates a molecular mechanism which might permit a refinement of such chronopharmacology," he said.

"Resetting the clock might have obvious application in the treatment of jet lag, but could also combine with existing knowledge to adjust circadian variability in drug response to the needs of a particular patient." McNamara likened the circadian systems to individual orchestra members, with the central clock as the band conductor. "If we understand which component needs to be regulated to reset the biological clock, we can target just that component with drugs," he said.

"Circadian oscillations may respond more directly to the environment. The central clock responds to changes in light intensity whereas in a vascular clock, this signal may be blood-borne hormones or metabolic signals." FitzGerald said in the particular case of the cardiovascular system "clocks probably evolved to protect the blood supply to individual organs from large shifts in blood pressure, such as might be caused by the adrenaline rush of danger or exercise."

Dr. Steven Reppert, professor and chairman of neuroscience at the University of Massachusetts Medical School in Worcester and a leader in the field of circadian rhythm studies, told UPI the study is "provocative" in that it describes, for the first time, a molecular peripheral signaling mechanism that can reset a circadian clock.

"This new mechanism for resetting a peripheral circadian clock suggests further exploration of whether or not there might be ways to actually reset the central clock in the brain," he said. "It remains to be seen whether there is a similar control mechanism in the central clock, but there's no reason to think that such a mechanism might not exist, and that's exciting."

At some point in the future, he said, it might even be possible to use certain drugs or vitamins to reset individual peripheral circadian clocks in the organs or even to reset one or more and leave the others alone. That might help avert jet lag or make adapting to shift work less taxing on the human body.

(Reported by UPI Medical Writer Kurt Samson in Washington.) Copyright 2001 by United Press International.

J Cell, 6/01


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