Induction of the Molecular Circadian Clock

描述（由申请人提供）：首席研究员是西北大学睡眠与昼夜生物学中心的研究助理教授。她寻求在昼夜节律分子遗传学方面的培训，以补充她目前的技能。她的长期目标是研究昼夜节律及其发展。昼夜节律是行为和生理上可预测的日常变化。在内部生物钟的驱动下，它们对疾病的诊断和治疗以及睡眠和情感障碍具有深远的临床意义。所有已知的生物钟的核心是一个细胞自主的转录反馈回路，在果蝇和小鼠之间保存得很好。这两个物种的核心成分都是生物钟（Clk）基因。在果蝇中，它的异位表达诱导了异位生物钟。本提案的直接研究目标是确定时钟基因在组织这些分子振荡中的作用，这是时钟发展的决定性步骤。具体来说，果蝇生物钟诱导的遗传需求将通过调节或与CLK配对的基因突变体中的异位CIk表达以及这些其他时钟基因的错误表达来测试。在组织内源性时钟方面，CIk的发育要求将通过使用分子遗传学方法在不同发育时期对Clk的条件拯救来检验。这些结果的普遍性将通过确定小鼠时钟基因的转基因表达是否能够在小鼠中诱导异位时钟来检验。这项研究将在西北大学进行，由国际知名的哺乳动物遗传学家J. Takahashi和正在崛起的年轻果蝇遗传学家R. Allada指导并合作进行。在这里，睡眠和昼夜生物学中心为生物节律训练提供了一个刺激和动态的环境。结合教学计划和个人指导，[候选人]将在果蝇和小鼠模型中获得昼夜节律分子遗传学的培训和经验。这些技术将补充她的解剖学技能。此外，在昼夜节律领域的培训将使她能够综合她以前工作的许多方面，包括脊椎动物和无脊椎动物对潜在行为的网络个体发生的研究。预计这将使她成为一名成熟的昼夜节律研究人员，研究生物钟的发展。

DESCRIPTION (provided by applicant): The principal investigator is a Research Assistant Professor in Northwestern University's Center for Sleep and Circadian Biology. She seeks training in the molecular genetics of circadian rhythms to complement her current skills. Her long-term goal is to study circadian rhythms and their development. Circadian rhythms are predictable daily changes in behavior and physiology. Driven by an internal biological clock, they have profound clinical relevance to diagnosis and treatment of disease and to sleep and affective disorders. The core of all known circadian clocks is a cell-autonomous transcriptional feedback loop, well-conserved between Drosophila and mice. In both species a central component is the Clock (Clk) gene. In flies its ectopic expression induces ectopic circadian clocks. The immediate research goal of this proposal is to determine the role of the Clock gene in organizing these molecular oscillations, a defining step in clock development. Specifically, genetic requirements for clock induction in Drosophila will be tested with ectopic CIk expression in mutants for genes that regulate or partner with CLK, and by misexpression of these other clock genes. A developmental requirement for CIk in organizing endogenous clocks will be examined by conditional rescue of Clk at various developmental times using molecular genetic approaches. The generality of these results will be tested by determining if transgenic expression of the mouse Clock gene is able to induce ectopic clocks in mice. The studies will be conducted at Northwestern University under the mentorship of and in collaboration with an internationally renowned mammalian geneticist (J. Takahashi) and a rising young fly geneticist (R. Allada). Here, the Center for Sleep and Circadian Biology provides a stimulating and dynamic environment for training in biological rhythms. In conjunction with a didactic program and individual mentoring, the [candidate] will gain training and experience in the molecular genetics of circadian rhythms in fly and mouse models. These techniques will complement her anatomical skills. In addition, training in the field of circadian rhythms will allow synthesis of many aspects of her previous work which include vertebrate and invertebrate studies on the ontogeny of networks underlying behavior. It is expected that this will allow her to develop into a mature circadian researcher studying the development of the biological clock.