The mammalian retina contains circadian clocks that regulate multiple aspects of retinal function by driving circadian rhythms of gene expression, photoreceptor outer segment membrane turnover, and visual sensitivity. Our long term goal is to understand how light and the circadian clocks control retinal and central nervous system functions, and the effects that disruption of this photic and circadian control has on the health and viability of neurons, especially photoreceptor cells. Our hypothesis is that a hierarchical network of clocks regulates circadian rhythms in the mammalian retina and the pacemaker controlling melatonin synthesis is the master circadian clock. Furthermore, we believe that melatonin plays and important role in photoreceptors viability and functioning. In the last few months we have developed a unique in vitro preparation and a series of transgenic mice in which the role of melatonin in the retina can be tested.
Three specific aims are designed to test this hypothesis.
In specific aim 1, we will determine if mouse photoreceptors contain the circadian pacemaker that drives melatonin synthesis.
In Specific aim 2, we will investigate the roles of melatonin in the generation of retinal rhythmicity by comparing melatonin proficient mice (C3H/f+/+) and melatonin receptor knock-out mice (MT1-/-, MT2-/- and MT1-/-MT2-/-) in C3H/f+/+. Finally, in specific aim 3 we will use melatonin receptor knock-out mice in C3H/f+/+ background to test the hypothesis that melatonin is important for photoreceptor functioning and viability. In our research, we will use a wide array of new and technologically advanced techniques, such as quantitative real time RT-PCR, laser capture dissecting microscopy, microarray analysis as well as real-time monitoring of bioluminescence rhythmicity in photoreceptor layers or isolated photoreceptor. Significance. Retinal circadian clock are involved in the modulation of many aspects of retinal physiology. Thus, understanding the cellular and molecular basis of retinal clock function will greatly improve our knowledge of retinal physiology and pathologies. Modern life style has tremendously changed the time at which we expose ourselves to light;hence, it is important to understand the effect that such exposure may have on retinal physiology and pathology.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Biological Rhythms and Sleep Study Section (BRS)
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Mitler, Merrill
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Morehouse School of Medicine
Anatomy/Cell Biology
Schools of Medicine
United States
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Tosini, Gianluca; Owino, Sharon; Guillaume, Jean-Luc et al. (2014) Understanding melatonin receptor pharmacology: latest insights from mouse models, and their relevance to human disease. Bioessays 36:778-87
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Pinotti, Mirko; Bertolucci, Cristiano; Frigato, Elena et al. (2010) Chronic sleep deprivation markedly reduces coagulation factor VII expression. Haematologica 95:1429-32

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