Genetic Defects of the Mammalian Circadian clock and Pre

描述(由申请人提供)：大量信息表明，从细菌到人类的生物体的生理和行为都受昼夜节律的控制，这些节律由内源振荡器驱动，对日常环境线索做出反应。第一个编码生物钟PERE(PER)分子的基因在果蝇中被发现。我的实验室帮助鉴定了两个哺乳动物时期的同源物，mPer1和mPer2。我们最近提供的遗传学证据表明，mPer1和mPer2确实是控制昼夜节律的关键角色。MPer2基因功能缺失突变导致昼夜节律失控。MPerl基因的缺失影响了时钟周期的精确控制，但突变动物保留了昼夜节律性。然而，mPer1和mPer2的丢失会导致生物钟活动完全消失。对这些时钟缺陷的动物，特别是那些带有mPer2突变的动物，一个有趣的观察是，它们显然过早衰老。在这项提议中，我们想要检验这样一种假设，即生物钟是与衰老有关的显性时钟。具体地说，我们想要了解线粒体动态平衡的生物钟控制。

DESCRIPTION (provided by applicant): A large body of information has indicated that the physiology and behavior of living organisms from bacteria to humans are controlled by circadian rhythms driven by endogenous oscillators in response to daily environmental cues. The first gene encoding a molecular player of the circadian clock, period (per) was identified in Drosophila. My laboratory was instrumental in the identification of two mammalian period homologue, mPerl and mPer2. We have recently provided genetic evidences that mPerl and mPer2 are indeed key players in the control of the circadian. Loss of function mutation of mPer2 gene results in the loss in control of circadian rhythmicity. The loss of mPerl gene affects the precision control of the clock period but the mutant animals retained circadian rhythmicity. However, a loss of both mPerl and mPer2 results in a complete absence of circadian clock activity. An interesting observation of these clock defective animals, especially those with mPer2 mutation is that they apparently age prematurely. In this proposal, we would like to test the hypothesis that the circadian clock is an overt clock involved in aging. Specifically we would like to understand circadian clock control of mitochondria homeostasis.