AGING AND CIRCADIAN RHYTHMS IN THE TAU MUTANT HAMSTER

TAU 突变仓鼠的衰老和昼夜节律

• 批准号: 3122840
• 负责人: FRED W TUREK
• 金额: $ 19.27万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 1996-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3122840
• 关键词: aging; body physical activity; circadian rhythms; gene mutation; hamsters; longevity; nervous system transplantation; suprachiasmatic nucleus

The first (and only) single gene mutation in a mammalian circadian system has recently been discovered in the golden hamster, this mutation alters the period of the circadian clock (the endogenous period under free- running conditions is reduced from the normal 24 hrs to about 20 hrs) and the response of the clock to the phase shifting effects of light and activity-inducing stimuli. These effects on the circadian clock are associated with ,.about a 50% decrease in the lifespan of the mutant hamsters. The overall objectives of the proposed studies are to determine 1) if decreased longevity in tau mutant hamsters is due to genetic or environmental factors, 2) if age-related changes in the circadian clock system occur at an earlier age in tau mutant animals, 3) what effect the tau mutation has on the timing of age-related changes in the circadian clock system, and 4) if longevity is reduced in the tau mutant animal because of the mutation's effects on the circadian clock itself. To reach these objectives, the circadian rhythm of locomotor activity will be used as a marker rhythm for the state of the circadian clock located in the suprachiasmatic nucleus (SCN) that underlies most behavioral and physiological rhythms in mammals. In one series of experiments, male and female wild-type and tau mutant hamsters will be exposed to either constant light (LL) or light-dark (LD) cycles in the two circadian ranges (i.e. 20 or 24-hr LD cycles) to determine if the decreased lifespan in the mutant animals is due to an intrinsic genetic effect on longevity or to the inability of the circadian clock of mutant animals to entrain normally to the standard 24-hr light cycle. In a second series of experiments, the effects of age on 1) the period of the clock, 2) the phase relationship of the activity rhythm to entraining light-dark cycles, 3) the rate of reentrainment following phase shifts in the light-dark cycle, and 4) the response of the circadian clock to light pulses or to a variety of activity-inducing stimuli will be determined in wild-type and tau mutant hamsters. The results of these studies will establish whether a mutation in the circadian system has an effect on normal age-related changes in the circadian clock system, as well as whether such changes occur at an earlier age in the mutant hamsters that corresponds in time with the decreased lifespan of the animals. In a third series of experiments, the effects of destruction of the circadian clock in the SCN on longevity will be established in order to determine if changes in the clock itself are responsible for the reduced lifespan of the mutant animals. A final series of experiments involving the transplantation of fetal SCN tissue from both wild-type and mutant hamsters to animals of the same or different genotype will be carried out to determine the role of transplanted SCN tissue in the restoration of circadian function in old hamsters. In view of the central role played by the circadian clock in the regulation of diverse biological systems, age-related changes in the clock can be expected to have a major impact on the health of the organism. A variety of circadian abnormalities have been found in elderly humans, including those suffering from Alzheimer's disease and disturbances of the sleep-wake cycle. Studies on how circadian mutations affect age-related changes in the circadian clock and whether circadian disturbances induced by mutations affect aging itself, may provide new information on the underlying physiological bases for age-related dysfunction within the circadian system and how altered clock function may contribute to the aging process.

哺乳动物昼夜节律系统中第一个(也是唯一一个)单基因突变 最近在金黄仓鼠身上发现，这种突变改变了 生物钟的周期(自由活动状态下的内生周期) 运行条件从正常的24小时减少到约20小时)和 时钟对光和光的相移效应的响应 活动诱导刺激。这些对生物钟的影响是 与突变体的寿命减少约50%有关 仓鼠。拟议研究的总体目标是 确定1)tau突变仓鼠寿命的降低是否归因于 遗传或环境因素，2)如果年龄相关的变化 Tau突变动物的生物钟系统出现在较早的年龄，3) Tau突变对年龄相关变化的时间有什么影响 昼夜节律时钟系统，以及4)如果tau的寿命减少 突变动物，因为突变对生物钟的影响 它本身。 为了达到这些目标，运动活动的昼夜节律 将被用作生物钟状态的标记节奏 位于视交叉上核(SCN) 哺乳动物的行为和生理节律。在一系列 实验中，雄性和雌性野生型和tau突变仓鼠将被 暴露在恒定的光(LL)或明暗(LD)循环中 两个昼夜节律范围(即20或24小时LD周期)，以确定 突变动物寿命的缩短是由于一种内在的遗传 对变种人的寿命或生物钟失灵的影响 动物被正常缠绕到标准的24小时光周期。在一个 第二系列实验，年龄对1)年龄周期的影响 时钟，2)活动节律与夹带的相位关系 光-暗循环，3)相移后的再卷吸速率 明暗循环，以及4)生物钟对光的反应 脉冲或各种活动诱导刺激将在 野生型和tau突变仓鼠。这些研究的结果将 确定昼夜节律系统中的突变是否对 昼夜节律时钟系统的正常年龄相关变化，以及 这种变化是否发生在较早年龄的突变仓鼠中 在时间上与动物寿命的缩短相对应。在一个 第三系列实验，昼夜节律的破坏效应 在SCN上建立关于长寿的时钟将会确定 如果时钟本身的变化导致寿命缩短 突变的动物。最后一系列实验涉及到 野生型和突变型胎儿SCN组织的移植 仓鼠对相同或不同基因型别的动物进行 确定移植的SCN组织在修复牙周炎中的作用 老年仓鼠的昼夜节律功能。 鉴于生物钟在生物钟中的中心作用 调节不同的生物系统，与年龄相关的变化 可以预期时钟会对人的健康产生重大影响 有机体。已发现多种昼夜节律异常。 老年人，包括那些患有阿尔茨海默病和 睡眠-觉醒周期的紊乱。昼夜节律突变的研究 影响昼夜节律的年龄相关变化，以及昼夜节律是否 突变引起的干扰会影响衰老本身，可能会提供新的 关于与年龄相关的潜在生理基础的信息 昼夜节律系统内的功能障碍和改变的时钟功能 可能会导致衰老过程。