MECHANISMS OF CIRCADIAN CLOCK OUTPUT

昼夜节律时钟输出机制

• 批准号: 7565887
• 负责人: Paul H Taghert
• 金额: $ 40.67万
• 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/7565887
• 关键词: Address; Applications Grants; Behavior; Behavioral; Brain; Calcitonin; Categories; Cell Culture Techniques; Cell Nucleus; Cells; Circadian Rhythms; Clinical; Complex; Cyclic AMP; Disease; Drosophila genus; Event; Face; Family; Family member; Fluorescence Resonance Energy Transfer; Foundations; G Protein-Coupled Receptor Genes; Genetic; Glutamates; Goals; Grant; Homologous Gene; In Vitro; Jet Lag Syndrome; Learning; Life; Measurement; Measures; Methods; Modeling; Molecular; Neurons; Neuropeptides; Neurotransmitters; Operative Surgical Procedures; Outcome; Output; Pacemakers; Peptides; Periodicity; Pigments; Process; Protein Isoforms; Proteins; Reagent; Receptor Signaling; Regulation; Reporter; Research; Resolution; Schedule; Secretin; Signal Transduction; Somatostatin; System; Testing; Time; Travel; Work; base; circadian pacemaker; cognitive function; in vitro Model; in vivo; interest; neural circuit; novel; peptide B; pituitary adenylate cyclase activating polypeptide; receptor; receptor coupling; receptor expression; relating to nervous system; research study; 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）：