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.
|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|
|Baba, Kenkichi; Benleulmi-Chaachoua, Abla; Journé, Anne-Sophie et al. (2013) Heteromeric MT1/MT2 melatonin receptors modulate photoreceptor function. Sci Signal 6:ra89|
|Tosini, Gianluca; Baba, Kenkichi; Hwang, Christopher K et al. (2012) Melatonin: an underappreciated player in retinal physiology and pathophysiology. Exp Eye Res 103:82-9|
|Baba, Kenkichi; Mazzoni, Francesca; Owino, Sharon et al. (2012) Age-related changes in the daily rhythm of photoreceptor functioning and circuitry in a melatonin-proficient mouse strain. PLoS One 7:e37799|
|Peachey, Neal S; Ray, Thomas A; Florijn, Ralph et al. (2012) GPR179 is required for depolarizing bipolar cell function and is mutated in autosomal-recessive complete congenital stationary night blindness. Am J Hum Genet 90:331-9|
|Tosini, Gianluca; Ye, Keqiang; Iuvone, P Michael (2012) N-acetylserotonin: neuroprotection, neurogenesis, and the sleepy brain. Neuroscientist 18:645-53|
|Alcantara-Contreras, Susana; Baba, Kenkichi; Tosini, Gianluca (2011) Removal of melatonin receptor type 1 increases intraocular pressure and retinal ganglion cells death in the mouse. Neurosci Lett 494:61-4|
|Sompol, Pradoldej; Liu, Xia; Baba, Kenkichi et al. (2011) N-acetylserotonin promotes hippocampal neuroprogenitor cell proliferation in sleep-deprived mice. Proc Natl Acad Sci U S A 108:8844-9|
|Sengupta, Anamika; Baba, Kenkichi; Mazzoni, Francesca et al. (2011) Localization of melatonin receptor 1 in mouse retina and its role in the circadian regulation of the electroretinogram and dopamine levels. PLoS One 6:e24483|
|Pinotti, Mirko; Bertolucci, Cristiano; Frigato, Elena et al. (2010) Chronic sleep deprivation markedly reduces coagulation factor VII expression. Haematologica 95:1429-32|
Showing the most recent 10 out of 36 publications