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）是主要的生物钟。依赖scn的生理和行为节律受环境光循环变化的调节。最近的研究表明，内源性SCN计时需要一个节律性转录调节程序，而光诱导的昼夜节律变化是由该转录程序的改变引起的。考虑到昼夜节律产生的转录基础，细胞内信号通路和下游转录因子参与生物计时的表征对于理解昼夜节律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器活性调节SCN中p42/44丝裂原活化蛋白激酶（MAPK）信号转导通路的激活状态。MAPK信号转导通路是多种转录因子的有效调节剂，并已被证明在某些形式的神经元可塑性中发挥作用。这些观察结果使我们假设MAPK途径将光输入与时钟夹带耦合，并且通过MAPK途径发出的信号作为时钟的输出途径。在Aim 1中，我们讨论了MAPK信号通路是否需要内源性时钟定时。我们还将研究MAPK信号通路中断后昼夜节律调节基因的表达，并确定受MAPK信号通路调节的转录因子。在Aim 2中，我们研究了MAPK信号是否将光刺激与生物钟的相移联系起来。我们还将研究MAPK通路是否将光刺激与SCN中的转录激活结合起来。在Aim 3中，我们研究了激活和灭活SCN中MAPK通路的细胞机制。识别调节SCN节律产生和生物钟光携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.