Genetic and phenotypic characterization of catnap, a novel short-sleeping mutant

描述（由申请人提供）：新兴数据表明睡眠在人类健康中的重要作用。尽管睡眠很重要，但它的功能仍然是神经生物学最大的谜团之一。由于缺乏对睡眠的分子遗传机制的理解，我们对睡眠功能的基本认识以及对睡眠障碍的诊断和治疗的潜在新目标的认识受到了阻碍。为了确定睡眠调节所需的新基因，首席研究员吴博士对果蝇进行了前向基因筛选。通过筛选大约3000个突变系，他确定了10个短睡眠突变株。其中一种突变体在调节睡眠的多巴胺转运体中携带了一种新的突变，这一发现证实了这种方法的有效性。这项提议的目标是确定在最短睡眠者之一的突变基因，命名为catnap，并确定其表型背后的行为和信号机制。小睡突变体的基线睡眠严重减少，支离破碎。定位实验将catnap基因定位在大约600kb的间隔上。在Aim 1中，他将测试一个假设，即在小睡中看到的短睡眠表型是由唤醒阈值或睡眠稳态的变化引起的。由于小睡突变体的表型类似于操纵cAMP信号所看到的，在Aim 2中，他将测试午睡通过cAMP信号来调节睡眠的假设。在第三阶段，他将克隆在午睡中突变的基因，以确定睡眠调节所需的一种新的分子成分。这些研究将在Amita Sehgal博士的实验室进行，她是昼夜节律和睡眠研究的先驱。由Allan Pack博士领导的宾夕法尼亚大学睡眠医学部提供的培训环境对于学术睡眠医生的发展是理想的。这项培训经费将为吴博士学习行为实验的设计、执行和分析提供一个很好的工具，并促进他作为一名研究睡眠分子机制的内科科学家的独立职业过渡。Lay Description：由于缺乏对睡眠分子机制的理解，我们设计新的诊断工具和治疗睡眠障碍的能力受到了损害。为了确定对睡眠调节重要的分子，本提案将描述一种新的短睡眠苍蝇突变体。

DESCRIPTION (provided by applicant): Emerging data point to an important role for sleep in human health. Despite its importance, the function of sleep remains one of neurobiology's great mysteries. Our ability to gain fundamental insights into the function of sleep as well as potentially identify novel targets for the diagnosis and treatment of sleep disorders is hindered by our lack of understanding of the molecular genetic mechanisms underlying sleep. To identify novel genes required for sleep regulation, Dr. Wu, the principal investigator, has carried out a forward genetic screen in Drosophila. By screening approximately 3,000 mutant lines, he has identified 10 short-sleeping mutant strains. One of these mutants carries a novel mutation in a dopamine transporter known to regulate sleep, a finding which validates this approach. The goal of this proposal is to identify the gene mutated in one of the shortest sleepers, named catnap, and to determine the behavioral and signaling mechanisms underlying its phenotype. Catnap mutants have severely reduced and fragmented baseline sleep. Mapping experiments localize the catnap gene to an approximately 600 kb interval. In Aim 1, he will test the hypothesis that the short-sleeping phenotype seen in catnap is caused by changes in arousal threshold or sleep homeostasis. Because the phenotype of catnap mutants resembles that seen with manipulation of cAMP signaling, in Aim 2, he will test the hypothesis that catnap acts via cAMP signaling to regulate sleep. In Aim 3, he will clone the gene mutated in catnap, to identify a novel molecular component required for sleep regulation. These studies will be carried out in the laboratory of Dr. Amita Sehgal, a pioneer in circadian and sleep research. The training environment provided by the Division of Sleep Medicine at the University of Pennsylvania, led by Dr. Allan Pack, is ideal for the development of academic sleep physicians. This training grant will provide an excellent vehicle for Dr. Wu to learn about the design, execution, and analysis of behavioral experiments and facilitate his transition towards an independent career as a physician-scientist studying the molecular mechanisms underlying sleep. Lay Description: Our ability to design new diagnostic tools and treatments for disorders of sleep is impaired by our lack of understanding of the molecular mechanisms underlying sleep. To identify molecules important for sleep regulation, this proposal will characterize a novel short-sleeping fly mutant.