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。尽管睡眠的功能很重要，但它仍然是神经生物学的一个大谜团。我们获得对睡眠功能的基本见解以及潜在地识别用于诊断和治疗睡眠障碍的新靶点的能力受到我们对睡眠基础的分子遗传机制缺乏理解的阻碍。为了确定睡眠调节所需的新基因，首席研究员吴博士在果蝇中进行了正向遗传筛选。通过筛选大约3,000个突变株系，他鉴定出了10个短睡眠突变株。其中一个突变体携带一种已知调节睡眠的多巴胺转运蛋白的新突变，这一发现验证了这种方法。这项计划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。打盹突变体严重减少和分散的基线睡眠。定位实验将catnap基因定位到大约600 kb的间隔。在目标1中，他将检验一个假设，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catnap突变体的表型与操纵cAMP信号的表型相似，在目标2中，他将测试catnap通过cAMP信号调节睡眠的假设。在目标3中，他将克隆在打盹中突变的基因，以确定睡眠调节所需的新分子成分。这些研究将在昼夜节律和睡眠研究先驱Amita Sehgal博士的实验室进行。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是学术睡眠医生发展的理想选择。这笔培训补助金将为吴博士提供一个很好的工具，让他学习行为实验的设计、执行和分析，并促进他向独立职业的过渡，成为一名研究睡眠分子机制的医生兼科学家。铺设说明：我们设计新的诊断工具和治疗睡眠障碍的能力由于我们对睡眠的分子机制缺乏了解而受到损害。为了鉴定对睡眠调节重要的分子，该提案将描述一种新的短睡眠果蝇突变体。

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.