Chemical and Genetic Manipulation of Circadian Systems

描述(由申请人提供)： 在过去的十年里，我们对动物生物钟的分子机制的理解发生了一场革命，包括鉴定了至少七个不同的基因，它们是生物钟机制的基本元件(时钟、电子邮件、Perl、PER2、Cryptochromel、Cryptochrome2和Casein Kinase 1 epsilon)。随着这些时钟基因的最初发现，人们意识到并记录了昼夜节律表达的能力在整个身体中广泛存在。大多数外周器官和组织可以孤立地表达昼夜振荡，但仍然接受并可能需要来自体内视交叉上核(SCN)的主要昼夜起搏器的输入。中枢和外周昼夜节律振荡器的存在提出了许多新的问题和假设，涉及到系统的整合以控制生物体的行为状态。 这些关于时钟机制和昼夜节律系统组织的发现为应用尖端技术发现化学和遗传工具来操纵体外和体内的昼夜节律提供了一个独特的机会。组织特异性和条件性遗传工具将用于确定中枢和外周昼夜节律障碍对行为状态的影响(高桥项目)。小分子(McKnight计划)和分子靶标(Hgenesch计划)的发现将为操纵昼夜节律提供新的工具。中心时钟成分的新等位基因将被识别和表征(格林计划)，这将为时钟机制提供新的见解，并将提供新的方法来分析在McKnight和Hgenesch计划中确定的化学和遗传工具。这些工具还将在细胞和生物体层面上进行分析(Menaker和Block项目)。最后，将利用人类的生物钟基因变异和生物钟紊乱来交叉验证和分析分子、细胞和动物研究(Ptacek项目)中开发的化学和遗传工具。分子(小化学物质和基因工具)的发现应该会为最终将我们的生物钟知识转化为人类行为和疾病提供新的机会。

DESCRIPTION (provided by applicant): The last decade has witnessed a revolution in our understanding of the molecular mechanism of circadian clocks in animals, including the identification of at least seven different genes that are essential elements of the circadian clock mechanism (Clock, Email, Perl, Per2, Cryptochromel, Cryptochrome2 and Casein kinase 1 epsilon). With the initial discovery of these clock genes came the realization and documentation that the capacity for circadian expression is widespread throughout the body. Most peripheral organs and tissues can express circadian oscillations in isolation, yet still receive and may require input from the dominant circadian pacemaker in the suprachiasmatic nucleus (SCN) in vivo. The existence of both central and peripheral circadian oscillators raises a number of novel questions and hypotheses concerning the integration of the system to control the behavioral state of the organism. These discoveries on the clock mechanism and the organization of the circadian system have provided a unique opportunity to apply cutting-edge technology to discover both chemical and genetic tools to manipulate circadian rhythms both in vitro and in vivo. Tissue-specific and conditional genetic tools will be used to determine the consequences of central vs. peripheral circadian rhythm dysfunction on behavioral state (Takahashi project). The discovery of small molecules (McKnight project) and molecular targets (Hogenesch project) will provide new tools for manipulating circadian rhythms. New alleles of the central clock components will be identified and characterized (Green project) which will provide new insight into the clock mechanism and will provide new ways to analyze the chemical and genetic tools identified in the McKnight and Hogenesch projects. These tools will also be analyzed at the cellular and organismal level (Menaker and Block project). Finally, circadian clock gene variants and circadian disorders in humans will be utilized to cross validate and analyze the chemical and genetic tools developed in the molecular, cellular and animal studies (Ptacek project). The discovery of molecules (small chemicals and genetic tools) should provide new opportunities for the eventual translation of our knowledge of circadian clocks to human behavior and disease.