Role of mTOR in Circadian and Sleep Deregulation in Smith-Kingsmore Syndrome (SKS)

摘要 Smith-Kingsmore综合征（SKS）是一种新发现的遗传性疾病， 雷帕霉素（MTOR）基因的机制靶点。MTOR的功能是协调细胞内的能量水平 与细胞内稳态和生长有关。MTOR失调与各种病理状况有关， 包括脑功能障碍一个值得注意的例子是结节性硬化症，其中MTOR过度激活是由于 tsc 1/2突变导致自闭症、癫痫和大脑中的良性肿瘤。SKS的临床特征包括 在一些实施方案中，所述治疗包括但不限于脑畸形、巨头畸形、癫痫、癫痫发作、智力残疾、自闭症谱系障碍和发育迟缓。 我们最近的研究还揭示了SKS的新方面，包括睡眠/觉醒中断，摄食过多， 过度活跃和自我攻击，所有这些都表明体内平衡失调和下丘脑功能障碍。 我们的研究重点是昼夜节律和睡眠系统。睡眠/觉醒障碍普遍存在 在SKS患者中，这是患者和护理人员最关心的问题。睡眠不足反映了 大脑内的稳态失衡，加剧疾病状态。我们的长期目标是推动 了解SKS的病理生理学和机制。我们的核心假设是， SKS中MTOR的激活破坏细胞生理稳态，导致睡眠/觉醒的破坏， 其他功能。为了验证这一假设，我们将产生细胞和小鼠SKS模型，并研究 致病性SKS变体如何影响MTOR活性、昼夜节律、睡眠/觉醒稳态，以及 其他行为和认知功能。我们希望提供一个更好的理解的原则证明， 超越基因型的因果机制，使精确的医学治疗策略成为可能。的MTOR 抑制剂雷帕霉素影响睡眠时间/阶段和质量。值得注意的是，低剂量雷帕霉素，优化为 使MTOR活性正常化的特异性等位基因能够恢复患者的睡眠/觉醒模式， 改善其他临床特征。我们将探讨雷帕霉素的治疗方案，并检验这一假设， 通过使MTOR活性正常化，等位基因特异性低剂量雷帕霉素可以改善睡眠/觉醒和其他功能。 由于雷帕霉素影响睡眠时间和质量以及其他行为和认知功能，我们希望 扩展了睡眠/觉醒功能代表一种新的神经生理学生物标志物的概念， 雷帕霉素剂量、MTOR活性和CNS稳态。这项研究将为今后的研究奠定基础。 机制和治疗研究。此外，这项研究对其他研究具有直接和更广泛的影响。 包括TSC在内的MTOR病。

ABSTRACT Smith-Kingsmore Syndrome (SKS) is a newly discovered genetic disorder caused by mutations in the mechanistic target of rapamycin (MTOR) gene. MTOR functions to coordinate intracellular energy levels with cellular homeostasis and growth. MTOR deregulation is implicated in various pathological conditions, including brain dysfunction. A notable example is tuberous sclerosis, in which MTOR hyperactivation due to Tsc1/2 mutation causes autism, epilepsy, and benign tumors in the brain. Clinical features of SKS include macrocephaly, epilepsy, seizure, intellectual disability, autism spectrum disorder, and developmental delay. Our recent studies also revealed new aspects of SKS, including sleep/wake disruption, hyperphagia, hyperactivity, and self-aggression, all indicative of homeostatic imbalance and hypothalamic dysfunction. Our research has a central focus on the circadian and sleep systems. Sleep/wake disturbance is prevalent in SKS patients and represents a top concern of patients and caregivers. Sleep insufficiency reflects homeostatic imbalance in the brain, exacerbating disease states. Our long-term goal is to advance the understanding of the pathophysiology and mechanisms of SKS. Our central hypothesis is that chronic activation of MTOR in SKS disrupts cell physiological homeostatic, leading to disruption of sleep/wake and other functions. To test this hypothesis, we will generate cellular and mouse SKS models and investigate how the pathogenic SKS variants affect MTOR activity, circadian rhythms, sleep/wake homeostasis, and other behavioral and cognitive functions. We hope to provide proof of principle that a better understanding of causal mechanisms, beyond genotype, enables precision medicine treatment strategies. The MTOR inhibitor rapamycin impacts both sleep time/phase and quality. Notably, low-dose rapamycin, optimized for specific alleles to normalize MTOR activity, was able to restore the patient’s sleep/wake pattern, while improving other clinical features. We will explore rapamycin regimens and test the hypothesis that by normalizing MTOR activity, allele-specific low-dose rapamycin can improve sleep/wake and other functions. As rapamycin impacts sleep time and quality and other behavioral and cognitive functions, we hope to expand the concept that sleep/wake function represents a novel neurophysiological biomarker for rapamycin dosing, MTOR activity and CNS homeostasis. This research will lay the groundwork for future mechanistic and therapeutic research. Further, this research has direct and broader implications for other MTORopathies including TSC.