MECHANISMS OF CIRCADIAN CLOCK OUTPUT

昼夜节律时钟输出机制

• 批准号: 7753213
• 负责人: Paul H Taghert
• 金额: $ 39.36万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7753213
• 关键词: Address; Applications Grants; Behavior; Brain; Cell Culture Techniques; Cell Nucleus; Cells; Circadian Rhythms; Clinical; Cyclic AMP; Disease; Drosophila genus; Face; Fluorescence Resonance Energy Transfer; Genetic; Grant; In Vitro; Jet Lag Syndrome; Learning; Life; Measures; Methods; Modeling; Molecular; Names; Neurons; Neuropeptides; Neurotransmitters; Output; Pacemakers; Principal Investigator; Process; Proteins; Reporter; Research; Schedule; Signal Transduction; Testing; Time; Travel; Work; base; circadian pacemaker; cognitive function; in vivo; interest; neural circuit; novel; operation; programs; receptor; receptor expression; relating to nervous system; shift work; therapy development

DESCRIPTION (provided by applicant): We are interested in signaling mechanisms used by circadian pacemaker neurons to organize daily locomotor behavior. There has been tremendous progress in recent years to define the molecular basis of the cell autonomous clockwork mechanism. That definition has permitted the identification of the primary pacemaker clock neurons within the brain, and in turn presented the opportunity to re-examine fundamental issues concerning the neural basis of behavior. In the previous grant cycle, we identified the receptor for PDF, which is a primary transmitter in the Drosophila circadian neural circuit. That finding establishes a basis for the current grant application. We now propose to describe PDF receptor expression by several independent means. This information will be critical to help interpret PDF signaling that underlies daily locomotor rhythms. Second we will establish an in vitro cell culture model to explore how PDF synchronizes pacemaker neurons by regulating the circadian molecular oscillator mechanism. There is in vivo evidence that PDF delays the entry of PERIOD protein into the nucleus and that frames an explicit hypothesis to be tested. In the past year, we have adapted a novel genetic FRET reporter to measure cAMP levels in vivo real-time. Thus our third aims it to use this method to study PDF signaling dynamics in the living brain. Finally, we will expand our research focus beyond PDF by pursuing the candidacy of several additional neurotransmitters/ neuropeptides for their potential contributions to the operations of the Drosophila circadian neural circuit. The normal functioning of the circadian pacemaker mechanism is essential for proper daily coordination of body and cognitive functions. When the body's timekeeping mechanisms go awry, as in seasonal adaptive disorders or as a consequence of shift work schedules, clinical complications can result. The work we undertake will directly address the fundamental mechanisms that help synchronize the body's clockwork of neurons. The principles we help establish will be useful to develop therapies that can reverse these chronobiological disorders.We study signaling mechanisms used by circadian pacemaker neurons to organize daily locomotor behavior. We face numerous challenges to the body's normal timekeeping functions, including travel-related jet-lag, shift work schedules, and seasonal disorders. The major focus for our work concerns transmitter signaling by pacemaker neurons to help learn more about the processes that could help reverse such time-related disorders.

描述（由申请人提供）： 我们对昼夜节律起搏器神经元使用的信号传导机制感兴趣，以组织日常运动行为。近年来，取得了巨大的进步来定义细胞自动发条机制的分子基础。该定义允许识别大脑中主要的起搏器时钟神经元，进而提供了重新检查有关行为神经基础的基本问题的机会。在上一个赠款周期中，我们确定了PDF的受体，PDF是果蝇昼夜节律中的主要发射器。这一发现为当前赠款申请建立了基础。现在，我们建议通过几种独立的手段来描述PDF受体表达。该信息对于帮助解释日常运动节奏的PDF信号传导至关重要。 其次，我们将建立一个体外细胞培养模型，以探索PDF如何通过调节昼夜节律分子振荡器机制来同步起搏器神经元。有体内证据表明，PDF延迟了周期蛋白进入细胞核，并构成了要测试的明确假设。在过去的一年中，我们已经改编了一个新型的遗传品格记者，以实时测量camp层。因此，我们的第三个目的是使用这种方法研究活体大脑中的PDF信号传导动力学。最后，我们将通过追求其他几种神经递质/神经肽的候选者的资格来扩展我们的研究重点，从而将其对果蝇昼夜节神经回路的操作的潜在贡献。 昼夜节律起搏器机制的正常功能对于适当的人体和认知功能的适当协调至关重要。当人体的计时机制出现问题时，例如在季节性自适应障碍或由于轮班工作时间表的结果时，可能会导致临床并发症。我们从事的工作将直接解决有助于同步神经元发条的基本机制。我们帮助确定的原理对于开发可以扭转这些时间生物学疾病的疗法将是有用的。我们研究昼夜节律起搏器神经元使用的信号传导机制，用于组织日常运动行为。我们面对人体正常的计时功能面临许多挑战，包括与旅行相关的喷气机，轮班工作时间表和季节性疾病。 我们工作的主要重点涉及起搏器神经元的发射器信号传导，以帮助更多有关有助于扭转此类时间相关的疾病的过程的更多信息。