Prokineticin 2 and Suprachiasmatic Circadian Output

前动力蛋白 2 和视交叉上昼夜节律输出

• 批准号: 7093485
• 负责人: QUN-YONG ZHOU
• 金额: $ 35.72万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-24 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7093485
• 关键词: behavioral /social science research tag; behavioral genetics; biological signal transduction; circadian rhythms; drug administration rate /duration; eating; gene environment interaction; gene expression; genetic promoter element; genetically modified animals; immunocytochemistry; laboratory mouse; laboratory rat; messenger RNA; neuropeptide receptor; neuropeptides; neuropsychology; protein metabolism; psychic activity level; psychomotor function; psychopharmacology; radioimmunoassay; receptor expression; suprachiasmatic nucleus; thirst; visual deprivation; western blottings

DESCRIPTION (provided by applicant): Organization of physiology and behavior with recurring daily environmental conditions is an adaptation that occurs in essentially all living organisms. Circadian rhythms are regulated by three components: the circadian pacemaker, an input mechanism and an output mechanism. In mammals, the master pacemaker driving circadian rhythms resides in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. Environmental light-dark cycles entrain the SCN clock to the 24-hr day. Synchronization of SCN neurons leads to coordinated circadian outputs that regulate expressed rhythms. A clear view of molecular clock mechanisms within the SCN has emerged. The molecular clockwork of the SCN circadian clock consists of auto-regulatory transcriptional and translational feedback loops that have both positive and negative elements. Similarly, the signal pathway of how light input resets SCN clock to synchronize with the environmental light/dark cycle is also emerging. In contrast to molecular mechanisms of SCN pacemaker clockwork and input pathway, relatively little is known about the output mechanism by which the SCN circadian pacemaker sends timing information to control physiological and behavioral rhythms. Prokineticin 2 (PK2), a cysteine-rich protein, has recently been shown as a SCN output molecule that transmits the circadian locomotor rhythm. PK2 fulfill the criteria expected for a bona fide output molecule from SCN circadian clock: 1) PK2 is a secreted molecule; 2) The transcription of PK2 is regulated by core clock genes, and PK2 mRNA oscillates in the SCN with high magnitude; 3) The production of PK2 is responsive to light entrainment; 4) Receptor for PK2 is expressed in primary SCN output target areas; and 5) Intracerebroventricular (ICV) administration of PK2 at subjective night, when endogenous PK2 levels are low, suppressed high nocturnal wheel-running activity. We propose to further investigate the role of PK2 signaling in the output mechanism of the SCN circadian clock. Specifically, the rhythms of PK2 protein in the cell bodies, terminal areas of SCN neurons and cerebral spinal fluid will be investigated by quantitative immunocytochemistry and/or radioimmunoassay. Whether PK2 is the common signal that mediates the output of SCN circadian clock and light masking will be investigated. How the PK2 rhythmic output from the SCN responds to abrupt shifts of light/dark cycle will also be investigated. Moreover, the effects of PK2 on SCN circadian clock-controlled locomotor and sleep/wake rhythms will be investigated by acute and chronic infusion of PK2 and PK2 antagonist in rats. Furthermore, the PK2 gene will be disrupted in mice and its effect on SCN-controlled circadian behavioral rhythms as well as core SCN circadian loops will be examined. Finally, the SCN PK2 output pathway will be investigated by a genetic approach. These proposed studies should help us gain further insight into the mechanism of PK2 signaling in mediating the output of timing information from the SCN circadian crock, and could have a major impact on the future treatment of a number of circadian disorders such as jet-lag, shift work syndrome, and chronic insomnia

描述（由申请人提供）：生理和行为与经常性的每日环境条件的组织是一种适应，它在所有生物中都发生在所有生物体中。昼夜节律受三个组成部分的调节：昼夜节律起搏器，一种输入机制和输出机制。在哺乳动物中，驱动昼夜节律的主曲式制作者位于前下丘脑的核上核（SCN）中。环境灯光循环将SCN时钟夹在24小时的日期。 SCN神经元的同步导致调节表达节奏的协调昼夜节律输出。 SCN内的分子时钟机制的清晰视图已经出现。 SCN昼夜节律时钟的分子发条由具有正元素和负元素的自动调节转录和翻译反馈回路组成。同样，光输入如何重置SCN时钟以与环境光/黑暗周期同步的信号途径也正在出现。与SCN起搏器发条和输入途径的分子机制相反，对于SCN昼夜节律起搏器传达时间来控制生理和行为节奏的输出机制，相对较少了解。原蛋白2（PK2）是一种富含半胱氨酸的蛋白，最近已显示为传播昼夜节律节奏的SCN输出分子。 PK2满足SCN昼夜节律时钟的真正输出分子的预期标准：1）PK2是一个分泌的分子； 2）PK2的转录由核心时钟基因调节，而PK2 mRNA在SCN中的振荡幅度很高； 3）PK2的产生对夹带的响应敏感； 4）PK2的受体在初级SCN输出目标区域中表达； 5）脑室内（ICV）在主观之夜给予PK2时，当内源性PK2水平较低时，降低了高夜间车轮运行活动。我们建议进一步研究PK2信号在SCN昼夜节律时钟输出机理中的作用。具体而言，将通过定量免疫细胞化学和/或放射免疫测定法研究细胞体PK2蛋白的节奏，SCN神经元和脑脊髓液的末端区域。 PK2是否是介导SCN昼夜节律时钟和光掩蔽输出的常见信号。 SCN的PK2节奏输出如何响应光/黑暗周期的突然变化。此外，PK2对SCN昼夜节律控制的运动和睡眠/唤醒节律的影响将通过大鼠的急性和慢性输注PK2和PK2拮抗剂来研究。此外，将检查PK2基因对小鼠的影响，并将检查其对SCN控制的昼夜节律行为节奏以及核心SCN昼夜节律循环的影响。最后，SCN PK2输出途径将通过遗传方法研究。这些拟议的研究应有助于我们进一步深入了解PK2信号传导的机制，从而导致SCN Circadian Crock的计时信息输出，并可能对许多昼夜节律疾病的未来治疗产生重大影响