MELATONIN SYNTHESIS IN THE WILSONS DISEASE ANIMAL MODEL

描述（改编自申请人的摘要）：昼夜节律和 环境照明调节夜间褪黑激素的合成， 涉及人体生理学各个方面激素，包括 睡眠-觉醒周期和躁狂抑郁症。 了解 褪黑激素动态调节的细胞机制 生产中，采用消减杂交技术， 对于大鼠松果体中白天和晚上差异表达的信息， 腺。 使用这种技术，一种选择性剪接形式的威尔逊的 疾病基因（PINA）被发现是 在夜间松果体中表达显著。 组织分布和 PINA时间表达模式与血清素相同 N-乙酰转移酶（NAT），褪黑激素合成的限速酶， 提示PINA在褪黑激素产生中的作用。 朗埃文斯肉桂 (LEC)大鼠是Wilson病的动物模型，其中PINA是 变异了 初步研究表明，血清素NAT的活性是 羟吲哚-O-甲基转移酶的活性降低， （HIOMT）是褪黑激素合成中的第二种也是最后一种酶， 没有改变 该建议旨在进一步分析功能 LEC松果体中PINA突变的结果，并阐明分子生物学 这一缺陷背后的机制。

DESCRIPTION (Adapted from applicant's abstract): Circadian rhythms and environmental lighting regulate nightly synthesis of melatonin, the pineal hormone implicated in various aspects of human physiology including sleep-wakefulness cycle and manic-depressive illnesses. To understand the cellular mechanisms underlying the dynamic regulation of melatonin production, a substractive hybridization technique was employed to search for messages differentially expressed during day and night in the rat pineal gland. Using this technique, an alternatively spliced form of the Wilson's disease gene (PIneal Night-specific ATPase = PINA) was found to be prominently expressed in night pineal gland. Tissue distribution and temporal expression pattern of PINA are identical to that of serotonin N-acetyltransferase (NAT), the rate limiting enzyme in melatonin synthesis, suggesting a role of PINA in melatonin production. Long Evans Cinnamon (LEC) rats are animal models of the Wilson's disease in which PINA is mutated. Preliminary studies revealed that the activity of serotonin NAT is decreased in these rats while that of hydroxyindole-O-methyltransferase (HIOMT), the second and the last enzyme in melatonin synthesis, is unaltered. This proposal is designed to further analyze the functional consequence of PINA mutation in LEC pineal and to elucidate molecular mechanism underlying this defect.