Abstract

The proposed studies will test several hypotheses regarding melatonin receptors, with special focus on identifying the receptor which mediates circadian responses to the hormone. The pattern of receptor binding will be examined in the brain and other tissues of mice in which the Mel-1a melatonin receptor gene has been disrupted by homologous recombination in embryonic stem cells. Mel-1a """"""""knockout"""""""" mice will then be used to determine whether this receptor mediates circadian, vascular, retinal, and longevity responses to melatonin. The Mel-1a gene will be disrupted with a lacZ reporter gene to characterize cellular and developmental patterns of Mel-1a gene expression and to establish if the Mel-1a locus can be used to deliver exogenous genes to the SCN. The melatonin receptor expressed in the human SCN will be identified using molecular, developmental, and pharmacologic approaches.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK042125-08
Application #
2872190
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
Margolis, Ronald N
Project Start
1990-08-06
Project End
2001-01-31
Budget Start
1999-02-15
Budget End
2001-01-31
Support Year
8
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199

  Publications

Jin, Xiaowei; von Gall, Charlotte; Pieschl, Rick L et al. (2003) Targeted disruption of the mouse Mel(1b) melatonin receptor. Mol Cell Biol 23:1054-60
Gubitz, A K; Reppert, S M (2000) Chimeric and point-mutated receptors reveal that a single glycine residue in transmembrane domain 6 is critical for high affinity melatonin binding. Endocrinology 141:1236-44
Gubitz, A K; Reppert, S M (1999) Assignment of the melatonin-related receptor to human chromosome X (GPR50) and mouse chromosome X (Gpr50). Genomics 55:248-51
Strohmeier, G R; Lencer, W I; Patapoff, T W et al. (1997) Surface expression, polarization, and functional significance of CD73 in human intestinal epithelia. J Clin Invest 99:2588-601
Liu, C; Weaver, D R; Jin, X et al. (1997) Molecular dissection of two distinct actions of melatonin on the suprachiasmatic circadian clock. Neuron 19:91-102
Weaver, D R (1997) Reproductive safety of melatonin: a ""wonder drug"" to wonder about. J Biol Rhythms 12:682-9
Reppert, S M; Weaver, D R; Cassone, V M et al. (1995) Melatonin receptors are for the birds: molecular analysis of two receptor subtypes differentially expressed in chick brain. Neuron 15:1003-15
Weaver, D R; Deeds, J D; Lee, K et al. (1995) Localization of parathyroid hormone-related peptide (PTHrP) and PTH/PTHrP receptor mRNAs in rat brain. Brain Res Mol Brain Res 28:296-310
Levine, J D; Sauman, I; Imbalzano, M et al. (1995) Period protein from the giant silkmoth Antheraea pernyi functions as a circadian clock element in Drosophila melanogaster. Neuron 15:147-57
Strohmeier, G R; Reppert, S M; Lencer, W I et al. (1995) The A2b adenosine receptor mediates cAMP responses to adenosine receptor agonists in human intestinal epithelia. J Biol Chem 270:2387-94

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