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

描述(由申请者提供)：新兴数据表明睡眠在人类健康中扮演着重要的角色。尽管睡眠很重要，但它的功能仍然是神经生物学的一大谜团。我们对睡眠的分子遗传机制缺乏了解，阻碍了我们对睡眠功能的基本洞察以及潜在地确定睡眠障碍诊断和治疗的新靶点的能力。为了识别睡眠调节所需的新基因，首席研究员吴博士对果蝇进行了正向基因筛查。通过筛选大约3000个突变株系，他已经鉴定了10个短眠突变株。其中一个突变体携带着一种已知的调节睡眠的多巴胺转运体的新突变，这一发现证实了这种方法。这项建议的目标是确定最短睡眠者之一的突变基因，并确定其表型背后的行为和信号机制。猫午睡突变体严重减少和碎片化了基线睡眠。作图实验将Catnap基因定位在大约600kb的区间。在目标1中，他将检验这样一种假设，即小睡过短的表型是由觉醒阈值或睡眠动态平衡的变化引起的。由于猫午睡突变体的表型类似于cAMP信号的操纵，在目标2中，他将检验猫午睡通过cAMP信号调节睡眠的假设。在目标3中，他将克隆睡眠中突变的基因，以确定睡眠调节所需的一种新的分子成分。这些研究将在阿米塔·塞格尔博士的实验室进行，他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非常适合学术睡眠医生的发展。这笔培训补助金将为吴博士提供一个极好的工具，让他学习行为实验的设计、执行和分析，并促进他向独立的职业生涯过渡，成为一名研究睡眠分子机制的内科科学家。外行描述：由于我们缺乏对睡眠的分子机制的了解，我们设计新的睡眠障碍诊断工具和治疗方法的能力受到了损害。为了确定对睡眠调节重要的分子，这项提议将描述一种新的短眠苍蝇突变体。

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.