How do vri and Pdp1 regulate cricadian rhythms?

vri 和 Pdp1 如何调节昼夜节律？

• 批准号: 6474101
• 负责人: JUSTIN BLAU
• 金额: $ 28.22万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6474101
• 关键词: Drosophilidae; arthropod genetics; circadian rhythms; gene expression; immunoprecipitation; invertebrate locomotion; microarray technology; protein structure function; regulatory gene; sleep; transcription factor; wakefulness; yeast two hybrid system

DESCRIPTION (provided by applicant): One night of disturbed sleep is all it takes for us to realize how essential sleep is. Our long-term objectives are to understand the molecular signals that cause us to wake up and go to sleep. An internal body clock regulates sleep/wake cycles and many other daily (circadian) rhythms. We use the model system Drosophila, which has the best molecular characterization of the molecular clock that governs circadian rhythms. We have found clock roles for two related transcription factors, vrille (vri) and Pdp1 (Par domain protein 1). vri and Pdp1 expression oscillates in a clock-dependent manner. Cycling expression of vri and Pdp1 is required for circadian rhythmicity since flies that continuously express high levels of vri and Pdp1 become arrhythmic. This is because vri and Pdp1 feed back to the clock and regulate expression of the other clock genes, indicating vri and Pdp1 are themselves clock genes that constitute a previously unidentified loop within the central clock. vri and Pdp1 may also connect the central clock to output pathways regulating behavior. For vri, this may be partly by regulating levels of the Pigment Dispersing Factor neuropeptide, which is required for rhythmicity. Other output signals are also predicted. We will take molecular and genetic approaches to understand the roles of vri and Pdp1 in the central clock, and a genomic approach to ask how they may link the clock to behavior. Our specific aims are: (1) To understand how vri and Pdp1 regulate the central oscillator. Which central clock genes do VRT and PDP1 proteins regulate? Do VRI and PDPI proteins form a functional complex or do they compete for binding to target gene promoters? (2) To use a genomic approach to identify VRI and PDP1-regulated genes. Are any of these genes expressed in pacemaker cells, and do they connect cycling clock gene expression with rhythmic behavior? Which VRI target gene explains how increased vri levels indirectly suppress PDF levels post-transcriptionally. Most of the Drosophila clock genes have related mammalian genes that function similarly. Clock output signals we identify in Drosophila may, ultimately, be useful in human therapy.

描述(申请者提供)：一晚睡眠紊乱就够了。 让我们意识到睡眠是多么重要。我们的长期目标是 理解导致我们醒来和入睡的分子信号。一个 体内生物钟调节睡眠/醒来周期和许多其他日常活动 (昼夜节律)节律。我们使用的模型系统是果蝇，它有最好的 控制昼夜节律的分子钟的分子特征 节奏。 我们发现了两个相关转录因子vrille(Vri)的时钟作用。 Pdp1(PAR结构域蛋白1)。VRI和Pdp1的表达在 时钟依赖方式。需要VRI和Pdp1的循环表达式 自持续表达高水平VRI的苍蝇以来的昼夜节律 而Pdp1则会发生心律失常。这是因为VRI和Pdp1向时钟反馈 并调节其他时钟基因的表达，表明VRI和Pdp1是 它们自身对构成以前未知的循环的基因进行时钟控制 中央时钟。 VRI和Pdp1还可以将中央时钟连接到输出路径调节 行为。对于VRI，这可能部分是通过调节色素的水平来实现的。 分散因子神经肽，这是节律性所必需的。其他输出 信号也是可以预测的。我们将采用分子和遗传方法来 了解VRI和Pdp1在中央时钟中的作用，以及基因组 问他们如何将时钟与行为联系起来。我们的具体目标是： (1)了解VRI和Pdp1是如何调节中枢振荡器的。哪一个 中枢时钟基因由VRT和PDP1蛋白调控吗？DO VRI和PDPI蛋白 它们形成功能复合体还是竞争与靶基因的结合 启动子？(2)使用基因组方法鉴定VRI和PDP1调节的 基因。这些基因中有没有在起搏细胞中表达，它们之间有联系吗？ 自行车时钟基因表达与节律行为？VRI的哪个靶基因 解释增加的VRI水平如何间接抑制PDF水平 转录后。 大多数果蝇的时钟基因都有相关的哺乳动物基因发挥作用 同样的。我们在果蝇中识别的时钟输出信号最终可能是 在人类治疗中很有用。