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革命性的变化，包括鉴定出至少七种不同的基因，它们是生物钟机制的基本要素（Clock，Email，Perl，Per2，Cryptochromel，Cryptochrome2和Casein kinase 1）。随着这些生物钟基因的最初发现，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单独表达昼夜节律振荡，但仍然接收并可能需要来自体内视交叉上核（SCN）中的主导昼夜节律起搏器的输入。中枢和外周昼夜节律振荡器的存在提出了一些新的问题和假设，关于系统的整合，以控制生物体的行为状态。 这些关于生物钟机制和昼夜节律系统组织的发现提供了一个独特的机会，可以应用尖端技术来发现化学和遗传工具来操纵体外和体内的昼夜节律。将使用组织特异性和条件遗传工具来确定中枢与外周昼夜节律功能障碍对行为状态的后果（Takahashi项目）。小分子（McKnight项目）和分子靶点（Hogenesch项目）的发现将为操纵昼夜节律提供新的工具。中心时钟组件的新等位基因将被识别和表征（绿色项目），这将为时钟机制提供新的见解，并将提供新的方法来分析McKnight和Hogenesch项目中确定的化学和遗传工具。这些工具也将在细胞和生物体水平上进行分析（Menaker和Block项目）。最后，生物钟基因变异和人类生物钟紊乱将被用于交叉验证和分析分子、细胞和动物研究中开发的化学和遗传工具（Ptacek项目）。分子（小分子化学物质和遗传工具）的发现应该为我们的生物钟知识最终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.