Induction of the Molecular Circadian Clock

描述（由申请人提供）：主要研究者是西北大学睡眠和昼夜节律生物学中心的研究助理教授。她寻求在昼夜节律的分子遗传学培训，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。昼夜节律是可预测的日常行为和生理变化。在内部生物钟的驱动下，它们与疾病的诊断和治疗以及睡眠和情感障碍具有深刻的临床相关性。所有已知的生物钟的核心是一个细胞自主的转录反馈环，在果蝇和小鼠之间非常保守。在这两个物种中，一个中心组成部分是Clock（Clk）基因。在果蝇中，其异位表达诱导异位生物钟。该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。具体而言，在果蝇中的时钟诱导的遗传要求将测试与异位CIK表达的突变体的基因，调节或合作伙伴与CLK，并通过这些其他时钟基因的错误表达。将使用分子遗传学方法通过在不同发育时间条件性拯救Clk来检查Clk在组织内源性时钟中的发育要求。这些结果的一般性将通过确定小鼠Clock基因的转基因表达是否能够在小鼠中诱导异位时钟来测试。这些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）和年轻的果蝇遗传学家（R. Allada）。在这里，睡眠和昼夜节律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]将获得苍蝇和小鼠模型昼夜节律分子遗传学方面的培训和经验。这些技术将补充她的解剖技能。此外，在昼夜节律领域的培训将允许她以前的工作，其中包括脊椎动物和无脊椎动物的个体发育的网络基础行为的研究的许多方面的合成。预计这将使她发展成为一个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.