Sleep and Circadian Rhythms in Tuberous Sclerosis Complex

描述(申请人提供)：睡眠是一种普遍但神秘的动物行为。越来越多的证据表明，正常睡眠在健康和疾病中发挥着至关重要的作用。对于患有神经发育障碍的儿童，如结节性硬化症(TSC)，情况可能尤其如此。TSC是一种神经遗传综合征，由TSC1或TSC2基因突变引起，这些基因会导致癫痫、智力残疾和自闭症。据报道，50%-90%的TSC儿童存在睡眠障碍，并对日间行为、癫痫控制、代谢稳态和心理健康产生不利影响。对TSC和其他神经发育综合征的睡眠障碍的治疗受到了限制，因为对这些条件下睡眠障碍的机制基础缺乏根本的了解。TSC1和TSC2编码的蛋白质抑制哺乳动物雷帕霉素靶标(MTOR)的功能，mTOR是所有细胞中营养状态和合成代谢的保守和关键整合因子。利普顿博士使用小鼠的TSC模型，在TSC的病因和基本的昼夜节律时钟蛋白BMAL1之间建立了机制联系。这些发现导致假设TSC/mTOR通路对大脑中枢计时机制--下丘脑视交叉上核(SCN)的功能至关重要。为了验证这一假说，目前的指导训练计划有以下目标：(1)确定大脑的中央计时器-视交叉上核(SCN)中TSC/mTOR信号的必要性和充分性；(2)在体内证明TSC/mTOR/S6K1介导的关键时钟蛋白BMAL1磷酸化的生理需求；(3)确定TSC1/2在睡眠维持和动态平衡中的作用。这些研究将确定TSC/mTOR通路在调节睡眠和昼夜节律中的分子作用。这些研究将在波士顿儿童医院和贝丝-以色列女执事医学中心进行，由哈佛医学院赞助，由著名睡眠科学家和神经解剖学家Clifford Saper博士和儿童神经学家和了解TSC神经学基础的先驱Mustafa Sahin博士双重指导。查尔斯·切斯勒博士领导的哈佛睡眠医学部为睡眠科学和医学方面的多学科、跨机构的最高水平的学术培训提供了一个肥沃的环境。利普顿博士是一名儿童神经学家和睡眠专家，他的职业目标是成为一名独立的内科科学家，致力于了解睡眠和昼夜节律在神经发育障碍中的作用。这一指导奖将为利普顿博士提供实验设计和实践、教学论和数据分析方面的有组织的培训经验，这将极大地促进向独立内科科学家职业的过渡。

DESCRIPTION (provided by applicant): Sleep is a ubiquitous yet mysterious animal behavior. Mounting evidence points to a crucial role for normal sleep in health and disease. This may be especially true for children with neurodevelopmental disorders such as Tuberous Sclerosis Complex (TSC). TSC is a neurogenetic syndrome that results from mutations in either the Tsc1 or Tsc2 genes that cause epilepsy, intellectual disability, and autism. Sleep dysfunction is reported in 50-90% of children with TSC and adversely affects daytime behavior, seizure control, metabolic homeostasis and psychological well- being. Treatment of sleep disorders in TSC and other neurodevelopmental syndromes has been limited by a fundamental lack of understanding of the mechanistic underpinnings of sleep dysfunction in these conditions. The proteins encoded by Tsc1 and Tsc2 inhibit the function of the mammalian target of rapamycin (mTOR), a conserved and critical integrator of nutrient status and anabolism in all cells. Dr. Lipton has used mouse models for TSC to establish a mechanistic link between the causes of TSC and the essential circadian clock protein BMAL1. These findings lead to the hypothesis that the Tsc/mTOR pathway is critical to the function of the central timekeeping mechanism in the brain, the suprachiasmatic nucleus of the hypothalamus (SCN). To test this hypothesis, the current mentored training plan has the following aims: (1) Determine the necessity and sufficiency of Tsc/mTOR signaling in the brain's central timekeeper, the suprachiasmatic nucleus (SCN); (2) Demonstrate the physiological requirement for Tsc/mTOR/S6K1-mediated phosphorylation of the crucial clock protein BMAL1 in vivo; (3) Determine the roles of TSC1/2 in sleep maintenance and homeostasis. These studies will establish the molecular role of the Tsc/mTOR pathway in the regulation of sleep and circadian rhythms. These studies will be carried at Children's Hospital Boston and Beth-Israel Deaconess Medical Center within the auspices of Harvard Medical School, under the dual mentorship of Dr. Clifford Saper, a renowned sleep scientist and neuroanatomist, and Dr. Mustafa Sahin, a child neurologist and pioneer in the understanding of the neurological basis for TSC. The Harvard Division of Sleep Medicine under the direction of Dr. Charles Czeisler provides a fertile environment for multi-disciplinary, cross-institutional academic training in sleep science and medicine at the highest level. Dr. Lipton is a child neurologist and sleep specialist with the career goal of becoming an independent physician-scientist committed to understanding the role of sleep and circadian rhythms in neurodevelopmental disorders. This mentored award will provide Dr. Lipton the structured training experience in experimental design and practice, didactics, and data analysis that will greatly facilitate the transition to a career as an independent physician-scientist.