Molecular and Cellular Studies of Circadian Rhythms

描述（由申请人提供）：我们一直在使用果蝇作为模型系统研究昼夜行为节律的分子控制。最初在苍蝇中发现的基因同源物，现在已经与脊椎动物（包括鱼、青蛙、老鼠和人类）的节律行为和生理控制有关。我们建议调查的两个激酶，GSK-3和DBT，在果蝇和哺乳动物的时钟。我们的一些初步工作提出了一种新的方法来研究某些人类抑郁症。我们工作的其他方面可以从生物钟中确定新的输出途径，这些途径组织昼夜行为和生理反应。以下将被解决：（1）GSK 3是否有一个核心作用，在哺乳动物的钟表，因为它在果蝇？锂和丙戊酸，治疗双相情感障碍的首选药物，如何停止生物钟？(2)GSK-3是否通过磷酸化TIM影响飞行时钟？GSK-3活性是PER/TIM核转位所必需的吗？(3)TIM在哺乳动物的生物钟中有作用吗？(4)DBT的体外活性是什么？(5)DBT依赖的磷酸化是否调节PER的核积累？PER磷酸化如何影响TIM的磷酸化？(6)DBT与PER的物理联系是否将激酶的其他底物置于昼夜节律控制之下？

DESCRIPTION (provided by applicant): We have been studying the molecular control of circadian behavioral rhythms using Drosophila as a model system. Homologues of genes initially characterized in the fly, have now been linked to the control of rhythmic behavior and physiology in vertebrates, including fish, frogs, mice and humans. We propose investigations of two kinases, GSK-3 and DBT, in the clocks of Drosophila and mammals. Some of our preliminary work suggests a novel approach to the study of certain human depressive disorders. Other aspects of our work could identify new output pathways from the clock that organize circadian behavioral and physiological responses. The following will be addressed: (1) Does GSK3 have a central role in the mammalian clockworks as it does in Drosophila? How do lithium and valproic acid, preferred agents for managing bipolar disorder, stop the circadian clock? (2) Does GSK-3 affect the fly clock by phosphorylating TIM? Is GSK-3 activity required for PER/TIM nuclear translocation? (3) Does TIM have a role in the mammalian clock? (4) What are the in vitro activities of DBT? (5) Does DBT-dependent phosphorylation regulate nuclear accumulation of PER? How does PER phosphorylation influence phosphorylation of TIM? (6) Does DBT's physical association with PER put other substrates of the kinase under circadian control?