Indentifying New Genetic Targets to Help treat Sleep Disorders

Paul-项目1项目主任/首席调查员(最后、第一、中间)：MacLeish，Peter R.项目摘要(见说明)：在当今要求苛刻的24小时社会中，睡眠障碍的流行率继续增加；然而，针对这些障碍的有效治疗方法的发展并未跟上步伐。其中一个主要原因是，构成基本睡眠过程的许多遗传和分子途径仍未确定。正向遗传学方法已经为各种疾病产生了新的治疗目标和更有效的治疗方法；然而，在睡眠障碍的研究中，类似的里程碑一直难以实现。在过去的几年里，很明显，睡眠的遗传学是复杂的，涉及多个基因和基因相互作用，潜在的影响大小很小。更大规模的基因组方法可能会提供必要的力量，揭开睡眠过程背后的基因。在这项申请中，我们提出了一种利用近交系小鼠自然变异的正向遗传学方法。我们研究了14个近交系小鼠在睡眠充足和睡眠剥夺条件下的53种睡眠-觉醒表型。我们建议将这个数据集扩大到至少增加11个菌株，以便为后续重组杂交中的数量性状座位(QTL)分析和位置克隆提供足够的统计能力，以便从QTL向基因过渡。这项工作将结合一个基因易驯化的动物模型的比较表型的成熟范例和强大的基因图谱工具来识别新的睡眠调节基因。因此，这些实验不仅将识别新的睡眠基因，还将有助于验证和澄清先前定位的基因，这些基因的作用尚未明确。这项提议的附带好处包括潜在的识别嗜睡的实用生物标记物，这经常被认为是当代睡眠研究中最紧迫的需求之一。

Paul- Project 1 Program Director/Principal Investigator (Last, First, Middle): MacLeish, Peter R. PROJECT SUMMARY (See instructions): In today's demanding 24-hour society the prevalence of sleep disorders continues to increase; however, the development of effective treatments for those disorders has not kept pace. One of the primary reasons is that many of the genetic and molecular pathways that underlie basic sleep processes are still undefined. Forward genetics approaches have yielded novel therapeutic targets and more effective treatments for a variety of diseases; however, similar milestones in the study of sleep disorders have been elusive. It has become apparent in the last several years that the genetics of sleep are complex, involving multiple genes and gene interactions with potentially small effect sizes. Larger-scale genomic approaches are likely to provide the necessary power uncover the genes that underlie sleep processes. In this application we propose a forward genetics approach that takes advantage of natural variation occurring in inbred mice. We have characterized 53 sleep-wake phenotypes in 14 inbred mouse strains in sleep-replete and sleep-deprived conditions. We propose to expand this dataset to add a minimum of 11 additional strains to provide sufficient statistical power for quantitative trait loci (QTL) analysis and positional cloning in subsequent recombinant hybrid crosses to transition from QTL to gene. This endeavor will combine a well-established paradigm of comparative phenotyping of a genetically tractable animal model with powerful genetic mapping tools to identify novel sleep regulatory genes. Consequently, these experiments will not only identify new sleep genes, they will also help verify and clarify previously mapped genes whose roles are not yet clearly defined. Ancillary benefits of this proposal include the potential identification of practical biomarkers of sleepiness, which is often cited as one of the most pressing needs in contemporary sleep research.