Molecular Analysis of Arabidopsis Circadian Regulation

描述(申请人提供)：昼夜节律，在生理和行为上大约24小时节律，在自然界中广泛存在，可以在许多植物和动物中找到。昼夜节律的紊乱与人类健康障碍有关，从时差到睡眠和情绪障碍，甚至癌症。在真核生物中，驱动这些节律的昼夜节律是由相互关联的转录反馈环组成的网络，在这些网络中，积极因素诱导消极因素的表达，而消极因素反过来抑制积极因素的表达。虽然不同王国之间的个体时钟成分并不保守，但在生物钟系统的组织和不同生物体之间的中央时钟或振荡器的“连接”之间，可以得出明确的类比。对生物钟如何在各种模型系统中工作的基本理解将导致对人类生物钟系统的功能及其在人类健康和疾病中的作用的新的见解。这项拟议研究的长期目标是更好地了解真核生物昼夜节律的分子基础。这些研究将在拟南芥中进行，这是一种模式生物，拥有广泛的遗传和基因组资源，非常适合进行昼夜节律研究。拟南芥中心时钟的一些预测成分尚未确定，许多已知时钟基因的生化功能尚未确定，也不清楚该时钟如何调控生长发育。拟议的研究将使用遗传、基因组和生化技术来解决这些基本问题。首先，在真核生物中高度保守的时钟相关蛋白的分子功能将由拟南芥和分裂酵母的遗传和生化研究相结合来确定。其次，将克隆一个与中枢时钟接近的基因，并对其进行鉴定。最后，将确定时钟调节转录因子的靶标，该转录因子调节中央时钟并调节器官大小。这些研究将对生物钟的工作方式以及它如何调节复杂的真核生物的生长和发育产生重要的见解，这些信息最终可能被用来通过治疗生物钟紊乱来改善人类健康。与公共健康相关：几乎所有的生物体都有一个内部时钟，可以在生理或行为上产生大约24小时的节律。扰乱人类的这种生物钟会产生严重的负面后果，导致睡眠和情绪紊乱，甚至可能导致癌症等疾病。为了更好地了解昼夜节律的分子基础，我们正在对模式生物拟南芥进行广泛的遗传、生化和基因组研究。

DESCRIPTION (provided by applicant): Circadian rhythms, roughly 24-hour rhythms in physiology and behavior, are widespread in nature and can be found in many plants and animals. Disruption of circadian rhythms has been linked to human health disorders ranging from jet lag to sleep and mood disorders and even to cancer. In eukaryotes, the circadian clocks that drive these rhythms are composed of networks of interlocked transcriptional feedback loops, in which positive factors induce the expression of negative factors that in turn repress expression of the positive factors. Although individual clock components are not conserved across kingdoms, clear analogies can be drawn between the organization of the circadian system and the `wiring' of the central clock, or oscillator, between disparate organisms. A fundamental understanding of how the circadian clock works in a variety of model systems will lead to new insights into the functioning of the human circadian system and its role in human health and disease. The long-term goal of the proposed research is to better understand the molecular basis of circadian rhythms in eukaryotes. These studies will be performed in Arabidopsis thaliana, a model organism with extensive genetic and genomic resources that is well-suited to circadian research. Some predicted components of the Arabidopsis central clock have not yet been identified, the biochemical functions of many known clock genes have not been determined, and it is not understood how the clock regulates growth and development. The proposed studies will use genetic, genomic, and biochemical techniques to address these fundamental questions. First, the molecular function of a clock-associated protein that is highly conserved across eukaryotes will be determined by a combination of genetic and biochemical studies in Arabidopsis and fission yeast. Second, a gene that acts close to the central clock will be cloned and characterized. Finally, the targets of a clock-regulated transcription factor that modulates the central clock and regulates organ size will be identified. These studies will yield important insights into the workings of the circadian clock and how it regulates growth and development in a complex eukaryote, information that ultimately may be used to improve human health through treatment of circadian disorders. PUBLIC HEALTH RELEVANCE: Almost all organisms possess an internal clock that generates roughly 24-hour rhythms in physiology or behavior. Disruption of this circadian clock in humans has serious negative consequences, causing sleep and mood disorders and perhaps even contributing to diseases such as cancer. To better understand the molecular basis of circadian rhythms, we are carrying out extensive genetic, biochemical, and genomic studies on the model organism Arabidopsis thaliana.