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Research on Your Ticker Clocks $1.5 Million Grant
Brown Foundation IMM scientist studies issues of timing in heart function, disease
The heart ticks to its own clock, a molecular timepiece that researchers say may help explain the higher incidence of early morning cardiovascular death and the greater risk of heart disease that threatens people who work different shifts.
Brown Foundation Institute of Molecular Medicine researcher Martin Young,
D.Phil., and second year medical student Nowice Trexler study rat heart
cells (on the screen at left) in Young’s lab. Trexler worked in the lab under
the UT Health Science Center at Houston’s Summer Research Program.
Photo by Jennifer Canup
University of Texas Health Science Center at Houston researcher Martin Young, D.Phil., suspects that anticipation might be the key, and is working to characterize the heart’s molecular circadian clock under a recently awarded $1.5 million grant from the National Heart, Lung and Blood Institute.
“Our hearts ‘wake up’ before we do. Our heart rate and blood pressure, for example, rise before we become conscious,” said Young, an assistant professor at the Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases. The circadian clock within the individual cells of the heart may play a role in this anticipatory phenomenon. By knowing the time of day, the heart can anticipate changes in its environment that occur in a 24-hour period.
“What then does the clock mechanism allow the heart to anticipate? It might be the availability of nutrients – we eat soon after awakening, for example, or a greater workload for the heart. Those are among the factors we are currently examining,” he said. “It is possible that the clock mechanism is abnormal in a diseased heart, preventing the heart from anticipating its environment. This may contribute to the progression of heart disease.”
Finding out how the heart clock “resets” each day, as well as identifying which environmental demands this mechanism allows the heart to anticipate, are major goals of Young’s research.
In a pair of scientific papers accepted in August for publication by the American Journal of Physiology – Endocrinology and Metabolism, Young and colleagues showed that expression of vital genes regulating the metabolism of fatty acids for nourishment of the heart vary regularly by time of day. These genes are most active in rats during their waking hours – at night. Paradoxically, fatty acids are most readily available in the bloodstream while the animals sleep, during the day for rats.
The heart draws 70 percent of its energy from fatty acids, Young said. The ability to efficiently process fatty acids that are available in the bloodstream upon awakening may be an evolutionary adaptation designed to help an animal endure an extension of its overnight fast while it forages for food, Young said.
Building on the findings in the first paper, Young and his colleagues identified another gene involved in fat metabolism that also is tuned to the circadian cycle.
Both papers have a practical message for scientists who study rodents: the time of day you collect your samples for analysis can affect your results. In this case, the gene was most active at night, when the rats were awake. Ending the experiment during the day would have missed that effect completely.
“Ending your experiments during regular working hours, for convenience sake, can lead to erroneous conclusions,” Young said. “Studying rats and mice at 3 p.m. is like studying humans at 3 a.m.”
The body’s central circadian clock is based in a part of the brain known as the suprachiasmatic nucleus, and is reset by daylight. However, molecular clocks have been identified in every cell investigated in the mammalian body to date, Young explained. These non-central clocks are known as peripheral clocks. When the central clock resets, it signals for the peripheral clocks to reset as well. Young wants to determine what signals reset the clock within the heart.
In rats, Young’s research will thoroughly characterize influences that drive the clock within the heart and the stimuli that the clock allows the heart to anticipate. Next, they will examine what happens when the heart clock is impaired, through manipulating the rats’ light-dark cycle, for example. These experiments may improve our understanding of the mechanisms responsible for increased heart disease in shift workers. Finally, the lab will generate and characterize genetically manipulated mice whose heart clock has been inactivated.
Young, who also holds a faculty appointment at the UT Graduate School of Biomedical Sciences at Houston, will examine the clock within both healthy and failing human hearts. In collaboration with Christine Moravec, Ph.D., of the Kaufman Center for Heart Failure at the Cleveland Clinic, Young has access to tissue samples from over 600 hearts. Some samples come from diseased hearts that were removed during transplantation, while others come from healthy hearts donated to science but not suitable for transplantation.
In both cases, the time of day at which the heart was procured is known, allowing Young to examine timedependent changes in gene expression between normal and failing human hearts. Linking disturbances in the clock mechanism within the heart to cardiovascular disease observed in the clinic is the ultimate goal.
— Scott Merville