Sleep and Circadian Rhythms in Tuberous Sclerosis Complex

描述（由申请人提供）：睡眠是一种普遍而又神秘的动物行为。越来越多的证据表明，正常睡眠在健康和疾病中起着至关重要的作用。对于患有神经发育障碍如结节性硬化症（TSC）的儿童尤其如此。TSC是一种神经遗传综合征，由引起癫痫、智力残疾和自闭症的Tsc1或Tsc2基因突变引起。据报道，50-90%的TSC患儿存在睡眠障碍，并对白天行为、癫痫发作控制、代谢稳态和心理健康产生不利影响。由于缺乏对这些情况下睡眠功能障碍的机制基础的理解，对TSC和其他神经发育综合征的睡眠障碍的治疗一直受到限制。Tsc1和Tsc2编码的蛋白抑制哺乳动物雷帕霉素靶蛋白（mTOR）的功能，雷帕霉素靶蛋白是所有细胞中营养状态和合成代谢的保守和关键整合体。Lipton博士使用小鼠TSC模型来建立TSC病因与基本生物钟蛋白BMAL1之间的机制联系。这些发现导致了Tsc/mTOR通路对大脑中央计时机制——下丘脑视交叉上核（SCN）的功能至关重要的假设。为了验证这一假设，目前的指导训练计划有以下目的：(1)确定大脑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在睡眠维持和体内平衡中的作用。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。这些研究将在哈佛医学院的赞助下，在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Mustafa Sahin博士的双重指导下，在波士顿儿童医院和Beth-Israel Deaconess医疗中心进行，Mustafa Sahin博士是了解TSC神经学基础的先驱。在Charles Czeisler博士的指导下，哈佛大学睡眠医学部为睡眠科学和医学的多学科、跨机构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科医生和睡眠专家，她的职业目标是成为一名独立的医生兼科学家，致力于了解睡眠和昼夜节律在神经发育障碍中的作用。这个导师奖将为Lipton博士提供实验设计和实践、教学和数据分析方面的结构化培训经验，这将极大地促进他作为一名独立的医生科学家的职业过渡。

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. PUBLIC HEALTH RELEVANCE: Project Narrative Sleep has emerged as a critical variable in human health. Sleep dysfunction adversely affects daytime behavior, seizure control, and metabolic parameters and is therefore of particular importance to children with neurodevelopmental disorders. This proposal investigates the biological mechanisms of sleep and circadian dysfunction in mouse models of the neurodevelopmental disorder Tuberous Sclerosis Complex. The goal of this work is to identify rational therapeutic targets that would ameliorate sleep dysfunction that accompany disorders of the developing brain and to fundamental mechanisms that regulate sleep and circadian rhythms.