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神经元用来组织日常运动行为的信号机制感兴趣。近年来，在定义细胞自主发条机制的分子基础方面取得了巨大进展。该定义允许识别大脑内的主要起搏器时钟神经元，反过来又提供了重新检查有关行为神经基础的基本问题的机会。在上一个资助周期中，我们鉴定了 PDF 的受体，它是果蝇昼夜节律神经回路中的主要递质。这一发现为当前的拨款申请奠定了基础。我们现在建议通过几种独立的方法来描述 PDF 受体的表达。这些信息对于帮助解释日常运动节律的 PDF 信号至关重要。 其次，我们将建立体外细胞培养模型，探索PDF如何通过调节昼夜分子振荡机制来同步起搏神经元。有体内证据表明 PDF 延迟了 PERIOD 蛋白进入细胞核的时间，这构成了一个待测试的明确假设。在过去的一年里，我们采用了一种新型基因 FRET 报告基因来实时测量体内 cAMP 水平。因此，我们的第三个目标是使用这种方法来研究活体大脑中的 PDF 信号动力学。最后，我们将通过寻求几种其他神经递质/神经肽的候选资格，扩大我们的研究重点，以了解它们对果蝇昼夜节律神经回路运作的潜在贡献。 昼夜节律起搏器机制的正常运作对于身体和认知功能的日常正常协调至关重要。当身体的计时机制出现问题时，例如季节性适应性障碍或轮班工作安排的结果，可能会导致临床并发症。我们所开展的工作将直接解决有助于同步人体神经元发条的基本机制。我们帮助建立的原则将有助于开发能够逆转这些时间生物学紊乱的疗法。我们研究昼夜节律起搏神经元用来组织日常运动行为的信号机制。我们的身体正常计时功能面临着诸多挑战，包括与旅行相关的时差、轮班工作安排和季节性失调。 我们工作的主要重点是起搏器神经元的发射信号传导，以帮助更多地了解有助于逆转此类与时间相关的疾病的过程。