Genetics of rest:activity behavior in the mouse

描述(由申请者提供)：我们研究的长期目标是确定参与调节REST的分子事件的遗传因素：小鼠的活动行为。我们使用正向遗传学的方法来识别导致活动水平或休息组织的总体变化的单基因突变：活动周期。这些变化可能是由于一般的代谢或发育缺陷，或由神经生物学过程中的异常引起的，如昼夜节律系统和睡眠调节。我们已经建立了一个整合和嵌套的表型方案，这将使我们能够在多个水平上表征新的突变；分子、神经病理、电生理和行为。我们的目标是：1)REST/活性突变体的遗传特征、定位和定位克隆，通过随机ENU(N-乙基-N-亚硝脲)突变鉴定；1)目的2)确定选定的REST：活性突变体的睡眠模式；目的3)确定REST的特异性：活性干扰；目的4)微阵列分析将用于确定被突变基因扰乱的下游通路。最初，该项目包括两个突变的遗传和表型特征，一个影响昼夜节律(公鸡)，另一个是疯人病，与昼夜节律幅度降低有关。 我们的假设是，Rest：Active突变的子集将发现涉及睡眠调节及其与其他神经生物学过程相互作用的新基因，例如那些构成学习和记忆或昼夜节律系统的基因。由这些单基因突变定义的人类基因座的直系同源基因可能代表了遗传性精神和睡眠障碍的多基因成分的相加或交互作用。

DESCRIPTION (provided by applicant): The long term goal of our studies is to identify genetic factors that underlie molecular events involved in the regulation of rest:activity behavior in the mouse. We employed forward genetics approach to identify single gene mutations that cause gross changes in activity levels or organization of rest:activity cycles. These changes may be due to general metabolic or developmental defects, or caused by anomalies in neurobiological processes, such as the circadian system and regulation of sleep. We have established an integrated and nested phenotypic protocol, which will allow us to characterize novel mutations on several levels; molecular, neuropathological, electrophysiological and behavioral. Our aims are: Aim 1) Genetic characterization, mapping and positional cloning of rest/activity mutants, identified by random ENU (N-ethyl-N-nitrosourea) mutagenesis; 1) Aim 2) Characterization of sleep patterns in selected rest:activity mutants; Aim 3) Determination of the specificity of rest:activity disturbances; Aim 4) Microarray analysis will be used to define downstream pathways disrupted by the mutant gene. Initially, this project includes genetic and phenotypic characterization of two mutations, one with an effect on circadian period (Rooster), and second, Bedlam, associated with a decreased amplitude of the circadian rhythms. Our hypothesis is that a subset of rest:activity mutations will uncover novel genes involved in the regulation of sleep and their interaction with the other neurobiological processes, such as those that underlie learning and memory or circadian system. Human orthologs of loci defined by these single gene mutations may represent additive or interactive contributions to the polygenic component of inherited psychiatric and sleep disorders.