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Neuropeptide Y (NPY) can alter circadian rhythms by directly resetting rhythms, or by blocking the resetting effects of light. Our current research uses several approaches to better understand these actions of NPY.
Using transgenic mice we can examine the behavioral and physiological consequences of loss of NPY or of a particular NPY receptor. Our lab has studied npy-/- mice as well as NPY receptor specific (Y1-/-, Y2-/- and Y5-/-) knockout mice. Some of this work is supported by a grant from the National Science Foundation (NSF RUI 0234203).
Pharmacological tools, such as blockers of specific NPY receptors, allow us to test hypotheses about the role of NPY at particular circadian phases or in interaction with other drugs or with light. We are collaborating with Pfizer, Inc. in some of these studies. We have discovered that combining NPY and serotonergic antagonists can greatly increase the action of light on the hamster circadian clock (Lall and Harrington, 2006). We are now testing these drugs at other times of day in work supported by the National Institutes of Health.
Here is a fantastic paper for background on circadian clock entrainment.
We are beginning studies to address the link between disruption of circadian rhythms and cancer. Our interest in this question comes from epidemiological studies that suggest a link between occupations that involve shift work or frequent jet lag and an increased incidence of cancer. Other studies indicate that patients with metastatic disease show better outcome if their circadian rhythms are more robust.
How might disruption of circadian rhythms alter the multitude of pathways that lead to cancer? We are conducting a study to determine if jet lag reduces the ability to respond to genetic damage. Our initial results were presented at the meeting of the Society for Research on Biological Rhythms in 2004.
Mary spent her sabbatical year 2005-6 in Toronto, working with Dr. Georg Bjarnason at Sunnybrook Hospital. Dr. Bjarnason is an oncologist and an expert on the topic of the impact of circadian clock disruption on cancer.
We acquired mice from Dr. Erik Herzog (Washington University) derived from mice from Dr. J. Takahashi (Northwestern University). These mice have a transgene inserted and produce a fusion protein, PER2::LUC. This transgene causes the production of luciferase and allows tracking of the circadian rhythm via production of the PER2 protein. We prepare tissue cultures from brain and body tissues from these mice and add luciferin to the culture medium, causing the tissue to emit light equivalent to the amount of luciferase produced. Light is detected using photomultiplier tubes within the LumiCycle, with a turntable device that allows us to monitor 32 cultures simultaneously. We are studying circadian rhythms in the SCN, liver, lung, testes, esophagus, spleen, mammary gland, and thymus. The phase and period varies in tissues throughout the body, but the SCN phase-leads most body organs.
We have collaborated with Dr. Chiaki Fukuhara to measure effects of altered kinase activation on circadian clock period in multiple tissues. In collaboration with Dr. Paola Yannielli we have measured effects of ghrelin, a peptide secreted by a hungry stomach, on circadian clock tissue. With the help of a summer student, Emily Moin, supported by HHMI, and in collaboration with Tanya Leise and Hava Siegelmann, we are using this technique in studies of jet lag. In work started by student Kate Dahlgren and continued this summer with Amherst College student Qingsi Zhu and Dr. Leise, we are studying aftereffects from entrainment to exotic T cycles. This work was funded by NSF 0423200, Smith College STRIDE, HHMI, and the Dean for Academic Development.
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