Genetic Defects of the Mammalian Circadian clock and Pre

哺乳动物昼夜节律钟的遗传缺陷和预

• 批准号: 6803008
• 负责人: CHENG CHI LEE
• 金额: $ 33.36万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6803008
• 关键词: T lymphocyte; aging; apoptosis; biological clocks; circadian rhythms; flow cytometry; free radical oxygen; gene expression; gene mutation; genotype; glutathione; ionizing radiation; laboratory mouse; microarray technology; mitochondria; polymerase chain reaction; posttranslational modifications; premature aging; psychobiology; terminal nick end labeling; thioredoxin

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.

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均受到昼夜节律的控制，而昼夜节律是由响应日常环境线索的内源性振荡器驱动的。第一个编码生物钟分子参与者 period (per) 的基因在果蝇中被发现。我的实验室在鉴定两种哺乳动物周期同源物 mPerl 和 mPer2 方面发挥了重要作用。我们最近提供的遗传证据表明 mPerl 和 mPer2 确实是控制昼夜节律的关键角色。 mPer2 基因功能缺失突变会导致昼夜节律失控。 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。然而，mPerl 和 mPer2 的丢失会导致生物钟活动完全消失。对这些生物钟缺陷动物（尤其是那些具有 mPer2 突变的动物）的一个有趣观察是，它们明显过早衰老。在这个提案中，我们想检验生物钟是与衰老有关的明显时钟的假设。具体来说，我们想了解线粒体稳态的生物钟控制。