Circadian Photoreception in Drosophila Melanogaster

果蝇的昼夜感光

• 批准号: 6720598
• 负责人: Patrick Emery
• 金额: $ 29.19万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6720598
• 关键词: Drosophilidae; biotechnology; chemical stability; circadian rhythms; conformation; ethology; functional /structural genomics; gene expression; gene mutation; genetic mapping; genetic screening; immunoprecipitation; light intensity; molecular genetics; phenotype; photoactivation; photobiology; protein binding; protein degradation; protein protein interaction; tissue /cell culture; visual pathways; visual photoreceptor; visual phototransduction; western blottings; yeast two hybrid system

DESCRIPTION (provided by applicant): Almost all organisms have an innate sense of time. From cyanobacteria to humans, intrinsic circadian clocks profoundly influence physiology and behavior on a 24-hour basis. For example, we sleep and wake every day at about the same time. Our knowledge of the molecular mechanisms underlying circadian rhythms in many organisms including humans has benefited immensely from the genetics of Drosophila melanogaster. Although we have a good understanding of how circadian oscillations are generated, we know little about the signal transduction mechanisms that synchronize the circadian clock with daily changes in light intensity. This is a fundamental question, because circadian rhythms need to be properly synchronized to be beneficial. In Drosophila melanogaster, a dedicated circadian light input pathway has been identified: CRY (CRYPTOCHROME) is the photoreceptor and TIM (TIMELESS) the target molecule within the pacemaker. We will use the powerful molecular, cellular and genetic tools that Drosophila offers to achieve our goal: understanding at a molecular level how light activates the CRY input pathway to synchronize the circadian pacemaker. Three major lines of investigation will be followed. The first aim will test the hypothesis that light triggers a change in CRY conformation that alters its stability and its ability to bind to target proteins. With the second aim, we will characterize genes identified as promising candidates for their involvement in the CRY light input pathway. Finally, with the third aim, we will identify novel components of this pathway by performing an unbiased screen for mutants that alter circadian photo responses. Combined, these approaches should fundamentally advance our understanding of circadian photoreception. Our work will also contribute to understanding general principles of circadian rhythm generation and the process of circadian entrainment. Recent appreciation of the clinical relevance of human circadian rhythms and the morbidity caused by their dysfunction, as occurs in shift workers, makes understanding of these basic mechanisms an important objective

描述（由申请人提供）：几乎所有生物体都有与生俱来的时间感。从蓝细菌到人类，内在生物钟二十四小时深刻地影响着生理和行为。例如，我们每天大约在同一时间睡觉和醒来。我们对包括人类在内的许多生物体昼夜节律分子机制的了解极大地受益于果蝇的遗传学。尽管我们对昼夜节律振荡是如何产生的有很好的了解，但我们对将生物钟与每日光强度变化同步的信号转导机制知之甚少。这是一个基本问题，因为昼夜节律需要正确同步才能有益。在果蝇中，已确定了专用的昼夜节律光输入途径：CRY (CRYPTOCHROME) 是光感受器，TIM (TIMELESS) 是起搏器内的目标分子。我们将利用果蝇提供的强大的分子、细胞和遗传工具来实现我们的目标：在分子水平上了解光如何激活 CRY 输入通路以同步昼夜节律起搏器。将遵循三个主要调查路线。第一个目标将测试光触发 CRY 构象变化的假设，从而改变其稳定性及其与目标蛋白结合的能力。第二个目标是，我们将鉴定被确定为有希望参与 CRY 光输入途径的候选基因的特征。最后，为了实现第三个目标，我们将通过对改变昼夜节律照片反应的突变体进行公正的筛选来识别该途径的新成分。结合起来，这些方法应该从根本上增进我们对昼夜感光的理解。我们的工作还将有助于理解昼夜节律产生的一般原理和昼夜节律夹带的过程。最近对人类昼夜节律的临床相关性及其功能障碍引起的发病率（如倒班工人中发生的情况）的认识，使得了解这些基本机制成为一个重要目标