MELATONIN SYNTHESIS IN THE WILSONS DISEASE ANIMAL MODEL

描述(摘自申请者的摘要)：昼夜节律和 环境照明调节夜间松果体褪黑激素的合成 荷尔蒙与人类生理的各个方面有关，包括 睡眠-觉醒周期和躁郁症。要了解 褪黑素动态调节的细胞机制 生产中，使用减数杂交技术进行搜索 大鼠松果体昼夜差异表达的信息 腺体。使用这种技术，威尔逊夫妇的另一种拼接形式 疾病基因(松果体夜间特异的ATPase=Pina)被发现是 在夜间松果体中有显著表达。组织分布和 PINA的时间表达模式与5-羟色胺的相同 N-乙酰转移酶(NAT)，褪黑素合成的限速酶， 这表明PINA在褪黑素的产生中起到了作用。长埃文斯肉桂 (LEC)大鼠是肝豆状核变性的动物模型 变异了。初步研究表明，5-羟色胺NAT的活性是 而羟基吲哚-O-甲基转移酶的活性 褪黑素合成的第二种也是最后一种酶(HIOMT)是 原封不动。本提案旨在进一步分析 PINA突变对LEC松果体的影响及分子机制探讨 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.