MAPK Signaling and Circadian Timing

描述（由申请人提供）：在哺乳动物中，下丘脑的视交叉上核（SCN）起主要生物钟的作用。SCN依赖的生理和行为节律受环境光周期变化的调节。最近的工作表明，一个程序的节奏转录调节所需的内源性SCN计时和光诱导的昼夜节律的变化，导致在这个转录程序的改变。鉴于昼夜节律产生的转录基础，生物计时中涉及的细胞内信号通路和下游转录因子的表征对于理解昼夜节律钟的功能特性至关重要。我们的初步研究表明，光刺激和内源性起搏活性调节SCN的p42/44丝裂原活化蛋白激酶（MAPK）信号转导通路的激活状态。MAPK信号转导途径是许多类转录因子的有效调节剂，并且已显示在某些形式的神经元可塑性中起作用。这些观察使我们假设MAPK通路将光输入耦合到时钟夹带，并且经由MAPK通路的信号传导充当来自时钟的输出通路。在目标1中，我们解决了MAPK信号通路是否需要内源性时钟定时。我们还将研究MAPK信号传导中断后昼夜节律调节基因的表达，并鉴定MAPK信号传导途径调节的转录因子。在目的2中，我们研究MAPK信号传导是否将光刺激与生物钟的相移相耦合。我们还将研究MAPK通路是否将SCN中的光刺激与转录激活偶联。在目的3中，我们研究了在SCN中激活和抑制MAPK通路的细胞机制。识别调节SCN节律产生和时钟光夹带的信号传导和转录途径将为昼夜节律相关疾病的治疗提供新的靶点。

DESCRIPTION (provided by applicant): In mammals, the suprachiasmatic nuclei (SCN) of the hypothalamus function as the major biological clock. SCN-dependent rhythms of physiology and behavior are regulated by changes in the environmental light cycle. Recent work has revealed that a program of rhythmic transcriptional regulation is required for endogenous SCN timekeeping and that light-induced changes in circadian timing result from alterations in this transcriptional program. Given the transcriptional basis of circadian rhythm generation, a characterization of the intracellular signaling pathways and downstream transcription factors involved in biological timing will be critical for understanding the functional properties of the circadian clock. Our preliminary studies reveal that photic stimulation and endogenous pacemaker activity regulate the activation state of the p42/44 mitogen-activated protein kinase (MAPK) signal transduction pathway in the SCN. The MAPK signal transduction pathway is a potent regulator of numerous classes of transcription factors and has been shown to play a role in certain forms of neuronal plasticity. These observations lead us to hypothesize that the MAPK pathway couples photic input to clock entrainment and that signaling via the MAPK pathway functions as an output pathway from the clock. In Aim 1 we address whether the MAPK signaling pathway is required for endogenous clock timing. We will also investigate the expression of circadian-regulated genes after disruption of MAPK signaling and identify transcription factors regulated by the MAPK signaling pathway. In Aim 2 we investigate whether MAPK signaling couples photic stimulation to phase shifting of the circadian clock. We will also investigate whether the MAPK pathway couples photic stimulation to transcriptional activation in the SCN. In Aim 3 we investigate cellular mechanisms that activate and inactivate the MAPK pathway in the SCN. Identification of the signaling and transcriptional pathways that regulate SCN rhythm generation and light-entrainment of the clock will provide new targets for therapeutic treatment of circadian-related ailments.