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

摘要 史密斯-金斯莫尔综合征(SKS)是一种新发现的遗传性疾病，由基因突变引起。 雷帕霉素(MTOR)基因的机制靶点。MTOR具有协调细胞内能量水平的功能 细胞的动态平衡和生长。MTOR的放松与各种病理情况有关， 包括大脑功能障碍。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 TSC1/2突变会导致自闭症、癫痫和脑部良性肿瘤。SKS的临床特征包括 巨头症、癫痫、癫痫、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/清醒中断、吞噬过度、 多动症和自我攻击性，所有这些都预示着体内平衡失衡和下丘脑功能障碍。 我们的研究主要集中在生理和睡眠系统上。睡眠/觉醒障碍很普遍 在SKS患者中，并代表了患者和照顾者的首要关注。睡眠不足反映了 大脑内的动态平衡失衡，加剧疾病状态。我们的长期目标是推进 对SKS的病理生理和发病机制有一定的了解。我们的中心假设是慢性 SKS中MTOR的激活破坏了细胞的生理动态平衡，导致睡眠/清醒和 其他功能。为了验证这一假设，我们将生成细胞和小鼠SKS模型，并研究 致病SKS变异如何影响MTOR活性、昼夜节律、睡眠/清醒动态平衡以及 其他行为和认知功能。我们希望提供原则性的证明，以便更好地理解 基因以外的病因机制的研究使精确的医学治疗策略成为可能。MTOR 雷帕霉素抑制剂会影响睡眠时间/阶段和睡眠质量。值得注意的是，低剂量雷帕霉素，优化为 使MTOR活性正常化的特定等位基因能够恢复患者的睡眠/清醒模式，而 改善其他临床特征。我们将探索雷帕霉素方案，并测试通过 通过使MTOR活性正常化，等位基因特异性的小剂量雷帕霉素可以改善睡眠/觉醒等功能。 随着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 扩展睡眠/觉醒功能代表一种新的神经生理生物标记物的概念 雷帕霉素用量、MTOR活性和中枢神经系统动态平衡。本研究将为今后的研究工作奠定基础 机械和治疗研究。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在内的地方性疾病。

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.