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: 6571447
• 负责人: CHENG CHI LEE
• 金额: $ 37.63万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 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 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6571447
• 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）：大量的信息表明，从细菌到人类的生物体的生理和行为是由响应日常环境线索的内源性振荡器驱动的昼夜节律控制的。第一个编码生物钟分子的基因，周期（per）是在果蝇中发现的。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参与者。mPer2基因的功能缺失突变导致对昼夜节律的控制丧失。mPerl基因的缺失影响了生物钟的精确控制，但突变动物保持了昼夜节律性。然而，mPerl和mPer2的缺失会导致生物钟活动的完全缺失。对这些生物钟有缺陷的动物，尤其是那些有mPer2突变的动物的一个有趣观察是，它们显然过早衰老。在这个提议中，我们想要测试生物钟是一个参与衰老的显性时钟的假设。具体来说，我们想了解线粒体稳态的生物钟控制。