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

描述（由申请人提供）：新数据表明睡眠在人类健康中发挥着重要作用。尽管睡眠的功能很重要，但它仍然是神经生物学的一大谜团。由于我们对睡眠背后的分子遗传机制缺乏了解，我们无法深入了解睡眠的功能，也无法确定诊断和治疗睡眠障碍的新靶点。为了鉴定睡眠调节所需的新基因，主要研究者吴博士在果蝇中进行了正向遗传筛选。通过筛选大约3000个突变株系，他鉴定出10个短休眠突变株系。其中一个突变体在已知调节睡眠的多巴胺转运蛋白中携带一种新的突变，这一发现验证了这种方法。该提案的目标是识别睡眠最短的人之一（称为“小睡”）的突变基因，并确定其表型背后的行为和信号机制。打瞌睡突变体的基线睡眠严重减少和支离破碎。作图实验将小睡基因定位在大约 600 kb 的间隔内。在目标 1 中，他将检验这样的假设：小睡中的短暂睡眠表型是由觉醒阈值或睡眠稳态的变化引起的。由于打瞌睡突变体的表型与控制 cAMP 信号传导所见的表型相似，因此在目标 2 中，他将测试打瞌睡通过 cAMP 信号传导调节睡眠的假设。在目标 3 中，他将克隆小睡中突变的基因，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 博士的实验室中进行。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对于学术睡眠医师的发展来说是理想的。这笔培训资助将为吴博士提供一个很好的工具，让他了解行为实验的设计、执行和分析，并促进他向独立职业生涯过渡，成为一名研究睡眠分子机制的医师科学家。外行描述：由于我们缺乏对睡眠分子机制的了解，我们设计新的睡眠障碍诊断工具和治疗方法的能力受到损害。为了识别对睡眠调节重要的分子，该提案将描述一种新型短睡眠果蝇突变体的特征。

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.