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. Previous work has shown that melatonin acting via g protein- coupled melatonin receptors (MTRs) plays a key role in the regulation of a wide variety of retinal circadian rhythms and melatonin is involved in the modulation of retinal cell viability during aging. In the present application we will further investigate the effect of MTR removal on the retina by using melatonin proficient mice (C3H-f+/+) mouse in which the two different types of g- protein coupled melatonin receptors (MTRs) have been removed. These new animal models developed in our laboratory provides a unique and powerful tool with which to investigate the role of melatonin and MTRs in the retina. Our preliminary data suggest that melatonin action within the some retinal cells is likely to be mediated via the formation of melatonin receptor 1 and 2 heteromers (MTRh). The present application comprises three specific aims.
In specific aim 1, we will determine whether melatonin receptor type 1 and melatonin receptor type 2 form heteromers in retinal cells.
In Specific aim 2, we will investigate the role of melatonin and its associated receptors in the regulation of the daily rhythms in disc shedding in melatonin proficient mice and melatonin receptor knock-out mice. Finally, in specific aim 3 we will determine whether administration of exogenous melatonin increase the sensitivity of the retina to light-induced damage via activation of MTRs and we will dissect the signaling pathways activate by melatonin in the photoreceptor and RPE cells. In our research, we will use a wide array of new and technologically advanced techniques, such as quantitative real time Q-RT- PCR, Bioluminescence Resonance Energy Transfert (BRET), laser capture dissecting microscopy, and microarray analysis. Significance. The characterization of the action of melatonin and its associated receptors may provide new and important insights on the mechanisms of action of melatonin in the eye and more in general in the rest of the body. The experiments proposed in our application will generate data that may lead to the development of new therapeutic tools to treat or prevent disease states associated with dysfunction of the melatonergic system.

Public Health Relevance

The characterization of the action of melatonin and its associated receptors may provide new and important insights on the mechanisms of action of melatonin in the eye and more in general in the rest of the body. The experiments proposed in our application will generate data that may lead to the development of new therapeutic tools to treat or prevent disease states associated with dysfunction of the melatonergic system.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY022216-10
Application #
8404013
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Greenwell, Thomas
Project Start
2012-01-01
Project End
2015-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
10
Fiscal Year
2013
Total Cost
$339,269
Indirect Cost
$88,706
Name
Morehouse School of Medicine
Department
Pharmacology
Type
Schools of Medicine
DUNS #
102005451
City
Atlanta
State
GA
Country
United States
Zip Code
30310
Sánchez-Bretaño, Aída; Baba, Kenkichi; Janjua, Uzair et al. (2017) Melatonin partially protects 661W cells from H2O2-induced death by inhibiting Fas/FasL-caspase-3. Mol Vis 23:844-852
Laurent, Virgine; Sengupta, Anamika; Sánchez-Bretaño, Aída et al. (2017) Melatonin signaling affects the timing in the daily rhythm of phagocytic activity by the retinal pigment epithelium. Exp Eye Res 165:90-95
Owino, Sharon; Sánchez-Bretaño, Aida; Tchio, Cynthia et al. (2017) Nocturnal activation of melatonin receptor type 1 signaling modulates diurnal insulin sensitivity via regulation of PI3K activity. J Pineal Res :
Tosini, Gianluca; Ferguson, Ian; Tsubota, Kazuo (2016) Effects of blue light on the circadian system and eye physiology. Mol Vis 22:61-72
Vancura, Patrick; Wolloscheck, Tanja; Baba, Kenkichi et al. (2016) Circadian and Dopaminergic Regulation of Fatty Acid Oxidation Pathway Genes in Retina and Photoreceptor Cells. PLoS One 11:e0164665
Jockers, Ralf; Delagrange, Philippe; Dubocovich, Margarita L et al. (2016) Update on melatonin receptors: IUPHAR Review 20. Br J Pharmacol 173:2702-25
Gianesini, Coralie; Hiragaki, Susumu; Laurent, Virginie et al. (2016) Cone Viability Is Affected by Disruption of Melatonin Receptors Signaling. Invest Ophthalmol Vis Sci 57:94-104
Baba, Kenkichi; Davidson, Alec J; Tosini, Gianluca (2015) Melatonin Entrains PER2::LUC Bioluminescence Circadian Rhythm in the Mouse Cornea. Invest Ophthalmol Vis Sci 56:4753-8
Evans, Jennifer A; Suen, Ting-Chung; Callif, Ben L et al. (2015) Shell neurons of the master circadian clock coordinate the phase of tissue clocks throughout the brain and body. BMC Biol 13:43
Kunst, Stefanie; Wolloscheck, Tanja; Kelleher, Debra K et al. (2015) Pgc-1? and Nr4a1 Are Target Genes of Circadian Melatonin and Dopamine Release in Murine Retina. Invest Ophthalmol Vis Sci 56:6084-94

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