Interdisciplinary studies of the Drosophila Circadian Clock

果蝇昼夜节律钟的跨学科研究

• 批准号: 7092488
• 负责人: Michael Warren Young
• 金额: $ 38.03万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-03 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7092488
• 关键词: Drosophilidae; behavior; circadian rhythms; emotions; flying; gene mutation; genes; lighting; phosphorylation; proteins

DESCRIPTION (provided by applicant): We have been studying the molecular control of circadian behavioral rhythms using Drosophila as a model system. Orthologs of genes initially characterized in the fly have now been linked to the control of rhythmic behavior and physiology in vertebrates, including fish, frogs, mice and humans. Here we propose three classes of interdisciplinary investigations of the Drosophila clock. (1) We will conduct collaborative structural studies that can help us determine how specific regulatory actions, previously recognized genetically and biochemically, are performed by certain domains of the PER protein. Does the structure of PER indicate how it interacts with TIM and DBT? Do such data suggest how TIM suppresses PER's phosphorylation by DBT? Does a putative LOV domain near the N-terminus of PER possess a flavin binding domain? (2) We will generate new mutations for the analysis of vital clock genes by Conditional Protein Splicing. Our studies of hyper- and hypo-morphic mutations of GSK-3, dbt, vri, and Pdp-1 indicate that each is a key component of the Drosophila clock. However, because null mutations of these genes are lethal, it has been difficult to determine their full effects on the clock. We are developing a form of chemical genetics in which small diffusible molecules will reversibly control the presence of each vital protein in living flies. (3) We will produce new micro array and statistical approaches to clarify features of rhythmic genome activity and to determine if flies use a single molecular mechanism to generate all circadian rhythms. To begin to link the clock to specific behavioral and physiological outputs, we will investigate a novel set of genes that are regulated by a paired action of light and the circadian clock.

描述（由申请人提供）：我们一直在研究使用果蝇作为模型系统的昼夜节律节奏的分子控制。最初以果蝇为特征的基因的直系同源物与控制脊椎动物的节奏行为和生理学的控制有关，包括鱼，青蛙，小鼠和人类。在这里，我们建议对果蝇时钟进行三类跨学科研究。 （1）我们将进行协作结构研究，以帮助我们确定以前在遗传和生化上认可的特定调节作用是由Per蛋白的某些域进行的。每个人的结构是否表明其与TIM和DBT的相互作用是如何相互作用的？这样的数据是否表明TIM如何抑制DBT的人均磷酸化？在每个人的N末端附近的假定LOV域是否具有黄素结合域？ （2）我们将通过条件蛋白剪接生成新的突变，以分析生命时钟基因。我们对GSK-3，DBT，VRI和PDP-1的超形和型突变的研究表明，它们都是果蝇时钟的关键组成部分。但是，由于这些基因的无效突变是致命的，因此很难确定它们对时钟的全部影响。我们正在开发一种化学遗传学的形式，其中小的扩散分子将可逆地控制生物中每个重要蛋白的存在。 （3）我们将产生新的微阵列和统计方法来阐明节奏基因组活性的特征，并确定苍蝇是否使用单个分子机制来产生所有昼夜节律。为了开始将时钟与特定的行为和生理输出联系起来，我们将研究一组新型的基因，这些基因受光和昼夜节律的配对作用调节。