The pineal gland is a neuroendocrine organ of the brain that synthesizes and releases melatonin, a nocturnal hormone important in seasonal reproduction, sleep, and pacemaker modulation. Melatonin production is controlled centrally by a biological clock in the suprachiasmatic nucleus (SCN) in the form of nightly norepinephrine release, and is the most reliable marker of the central pacemaker. Locally within the pineal gland, melatonin production is dictated by the combined action of cAMP signaling and pineal specific transcriptional activities.
The first focus of my lab is to investigate the properties of the central pacemaker by studying the melatonin output, the hands of the circadian clock under normal and perturbed conditions. To facilitate analysis of the central pacemaker, we have recently developed a long-term automated pineal microdialysis technique, which allows us to follow melatonin secretion from individual animals for long time with precision and high temporal resolution. Using this new approach, we have found novel features of the central pacemaker that have not been appreciated. We plan to investigate in detail the properties of entrainment and reentrainment of the circadian clock following light stimulation of various kinds.
The second focus of my lab is to study how circadian rhythms of melatonin production is regulated within the pineal gland. Our studies have demonstrated that melatonin production in rat pineal is determined by transcriptional activation of serotonin N-acetyltransferase (NAT) and that the rate of nocturnal melatonin production is limited by hydroxyindole-O-methyltransferase (HIOMT). Our plan is to study the temporal and spatial regulation of circadian melatonin production with an emphasis on identification of the key in vivo factors in regulating melatonin formation.
The third area of our research is focused on the role of PINA (Pineal Night specific ATPase, a novel variant of copper-transporting ATP7B that is defective in Wilson Disease) in circadian rhythm and Wilson disease. In the past few years, we have performed detailed molecular and physiological analysis of PINA mutant rats and concluded that PINA function is independent of melatonin formation. This discovery leads to an exciting possibility that the pineal may have novel circadian functions that require PINA. We will attempt to identify and isolate molecules that may be the product of PINA activity in the night pineal using a combination of molecular and biochemical techniques. Ultimately, we will manipulate these molecules in the intact animal to determine their physiological effects using real-time microdialysis. key words: circadian rhythms, biological clock, suprachiasmatic nucleus (SCN), pineal gland, melatonin, Pineal Night specific ATPase, Wilson Disease

Recent Publications:

Borjigin J, Wang MM, Snyder SH. Diurnal variation in mRNA encoding serotonin N-acetyltransferase in pineal gland.
Nature. 1995 Dec 21-28; 378(6559):783-5.
 
Li X, Chen S, Wang Q, Zack DJ, Snyder SH, Borjigin J. A pineal regulatory element (PIRE) mediates transactivation by the pineal/retina-specific transcription factor CRX.
Proc Natl Acad Sci U S A. 1998 Feb 17; 95(4):1876-81.

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