How do vri and Pdp1 regulate cricadian rhythms?

描述（由申请人提供）：一个晚上的睡眠不安是所有它 让我们意识到睡眠的重要性我们的长远目标是 了解导致我们醒来和入睡的分子信号。一个 内部生物钟调节睡眠/觉醒周期和许多其他日常生活 （昼夜）节律。我们使用果蝇模型系统，它有最好的 控制昼夜节律的分子钟的分子表征 节奏 我们发现了两个相关的转录因子vrille（vri）的时钟作用 和Pdp 1（Par结构域蛋白1）。vri和Pdp 1的表达呈周期性波动， 依赖时钟的方式。vri和Pdp 1的循环表达是 由于果蝇持续表达高水平的VRI 和Pdp 1成为免疫原性。这是因为vri和Pdp 1反馈到时钟 并调节其他时钟基因的表达，表明vri和Pdp 1是 它们自己的时钟基因构成了一个以前未被识别的循环， 中央时钟 vri和Pdp 1还可以将中央时钟连接到调节 行为对于vri，这可能部分是通过调节 分散因子神经肽，这是所需的节奏。其他输出 信号也被预测。我们将采用分子和遗传学方法， 了解vri和Pdp 1在中央时钟中的作用， 询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Pdp 1如何调节中央振荡器。这 VRT和PDP 1蛋白调节的中央时钟基因？VRI和PDPI蛋白 形成功能复合物还是竞争结合靶基因 促销员？(2)使用基因组方法鉴定VRI和PDP 1调节的 基因.这些基因中有没有在起搏细胞中表达， 生物钟基因表达与节律行为的关系VRI靶基因 说明增加的vri级别如何间接抑制PDF级别 转录后的 大多数果蝇的时钟基因都有相关的哺乳动物基因， 同样的。我们在果蝇中识别的时钟输出信号最终可能是 可用于人类治疗。

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.