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Margarita L. Dubocovich, PhDProfessor
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Our long term goal is to understand the function, signaling pathways and molecular properties of melatonin receptors, their interaction with dopamine receptors and their potential as therapeutic targets for the treatment depression, insomnia, circadian sleep disorders and cancer. The hormone melatonin is produced and secreted from the pineal gland following a circadian rhythm with high levels at night. It regulates a variety of physiological and neuroendocrine functions. Melatonin receptors [MT1, MT2] are members of the G protein-linked receptor family, are coupled to various signaling pathways. Melatonin also acts at putative cytosolic and nuclear melatonin receptors to mediate a variety of cellular effects.
Ongoing studies include melatonin receptor localization, pharmacological and molecular characterization and regulation of signaling pathways. The use of molecular based drug design is aimed towards the discovery of novel and receptor type selective ligands which are tested in in vitro bioassays (eg., suprachiasmatic nucleus brain slice) and in vivo animals models, including mice with genetic deletion of the MT1 and/or MT2 melatonin receptors, to assess their effects on behavioral and circadian rhythms paradigms. These novel molecules may have therapeutic potential to treat human circadian rhythms disturbances such as those observed in mood and sleep disorders of endogenous (blindness, aging, delay sleep phase syndrome) and exogenous (jet lag, phase shift) causes, cardiovascular disease and cancer. Clinical research studies use melatonin to treat sleep disorders in subjects with Delay Phase Sleep Syndrome and to augment the antidepressant effect of Prozac in subjects with major unipolar depression.
Dubocovich, M.L., Markowska, M. Functional MT1 and MT2 melatonin receptors in mammals. Endocrine 27:101-103, 2005 (Review)
Dubocovich, M.L., Hudson, R.L., Sumaya, I.A., Masana, M.I., Manna E.: Effect of MT1 melatonin receptor deletion on melatonin-mediated phase shift of circadian rhythms in the C57B6 mouse. J. Pineal Res. (Online publication: 23-Mar-2005), 39:113-120, 2005.
Sumaya, I.C., Masana, M.I., Dubocovich, M.L. Antidepressant-like effect of melatonin receptor antagonist luzindole in the forced swimming test in the C3H/HeN mouse lacking the MT1 receptor. J. Pineal Res. (Online publication: 23-Mar-2005), 39:170-177, 2005
DAVID E. BLASK, D.E., BRAINARD, G.C., DAUCHY, R.T., HANNIFIN, J., DAVIDSON, L.K., KRAUSE, J.A., SAUER, L.A., RIVERA-BERMUDEZ, M.A., DUBOCOVICH, M.L., JASSER , S.A., LYNCH , D.T., ROLLAG, M.D. AND ZALATAN, F. Light-induced nocturnal melatonin suppression is a new risk factor for human breast cancer. Cancer Res. 65:11174-11184, 2005.
MUNDEY, K., BENLOUCIF, S., HARSANYI, K., DUBOCOVICH, M.L., ZEE, P.C. Phase Dependent Treatment of Delayed Sleep Phase Syndrome with Melatonin. Journal SLEEP 28:1271-1278, 2005.
MASANA, M.I., SOARES, J.M., Jr., DUBOCOVICH, M.L. 17 b-Estradiol Modulates hMT1 Melatonin Receptor Function. Neuroendocrinology 81: 87-95, 2005.
HANSEN, M., JANSSEN, I., SCHIFF, A., ZEE,P.C. AND DUBOCOVICH, M.L. The Impact of School Daily Schedule on Adolescent Sleep. Pediatrics 115:1555-1561, 2005.
RIVERA-BERMÚDEZ, M.A., MASANA, M.I., BROWN, G.M., EARNEST, D.J., DUBOCOVICH, M.L. Immortalized Cells From The Rat Suprachiasmatic Nucleus Express Functional Melatonin Receptors. Brain Res. 1002: 21-27, 2004.
GERDIN, M.J., MASANA, M.I. and DUBOCOVICH, M.L. Melatonin-Mediated Regulation of Human MT1 Melatonin Receptors Expressed in Mammalian Cells Biochem. Pharmacol. 67:2023-2030, 2004.
GERDIN, M.J., MASANA, M.I., RIVERA-BERMÚDEZ, M.A., HUDSON, R.L., EARNEST, D.J., GILLETTE, M.U. and DUBOCOVICH, M.L. Melatonin Desensitizes Endogenous MT2 Melatonin Receptors in the Rat Suprachiasmatic Nucleus: Relevance for Defining the Periods of Sensitivity of the Mammalian Circadian Clock to Melatonin. FASEB J. 18:1646-1656, 2004.
RIVERA-BURMUDEZ, M.A., GERDIN, M.J., EARNEST, D.J., and DUBOCOVICH, M.L. Regulation of basal rhythmicity in protein kinase C activity by melatonin in immortalized rat suprachiasmatic nucleus cells. Neuroscience Letters 346:37-40, 2003.
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View Publications by Margarita Dubocovich listed in the National Library of Medicine (PubMed). |
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