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

mTOR 在史密斯-金斯莫尔综合征 (SKS) 昼夜节律和睡眠失调中的作用

• 批准号: 10586191
• 负责人: Andrew C. Liu
• 金额: $ 49.49万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586191
• 关键词: Address; Affect; Aggressive behavior; Alleles; Behavior; Behavioral; Benign; Biological Clocks; Biological Markers; Brain; Brain Neoplasms; Caregivers; Categories; Cell model; Cells; Central Nervous System; Chronic; Circadian Dysregulation; Circadian Rhythms; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Cognition; Data; Developmental Delay Disorders; Disease; Dose; Epilepsy; FRAP1 gene; Fasting; Foundations; Functional disorder; Future; Genes; Genetic; Genetic Diseases; Genotype; Goals; Growth; Homeostasis; Hyperactivity; Hyperphagia; Hypothalamic dysfunction; Impaired cognition; Intellectual functioning disability; Knock-in Mouse; Learning; Lentivirus; Link; Macrocephaly; Metabolic; Modeling; Motor Activity; Mus; Mutation; Nervous System Physiology; Neurocognitive Deficit; Pathogenicity; Pathologic; Pathway interactions; Patients; Pattern; Persons; Phase; Phenotype; Physiological; Physiology; Regimen; Regulation; Research; Role; Seizures; Sirolimus; Sleep; Sleep Deprivation; Sleep Wake Cycle; Sleep disturbances; Symptoms; Syndrome; System; TSC1 gene; Testing; Therapeutic Research; Time; Tissues; Tuberous Sclerosis; Variant; anxiety-like behavior; autism spectrum disorder; brain dysfunction; cell growth; circadian; circadian pacemaker; cognitive function; epileptiform; feeding; functional outcomes; gain of function; genetic variant; high risk; improved; improvement on sleep; inhibitor; insight; mTORopathies; molecular clock; mouse model; neurobehavior; neurophysiology; novel; pharmacologic; precision medicine; proteostasis; treatment strategy; variant of unknown significance

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.

抽象的 史密斯-金斯莫尔综合症（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) 基因的机制靶标具有协调细胞内能量水平的作用。 MTOR 失调与多种病理状况有关， 一个显着的例子是结节性硬化症，其中 MTOR 过度激活。 Tsc1/2 突变会导致自闭症、癫痫和大脑良性肿瘤，SKS 的临床特征包括。 大头畸形、癫痫、抽搐、智力障碍、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、食欲亢进、 多动和自我攻击，这些都是体内平衡失衡和下丘脑功能障碍的指标。 我们的研究重点是昼夜节律和睡眠系统，睡眠/觉醒障碍很普遍。 在 SKS 患者中，睡眠不足是患者和护理人员最关心的问题。 大脑稳态失衡，加剧疾病状态，我们的长期目标是促进疾病的发展。 我们对 SKS 的病理生理学和机制的理解是慢性的。 SKS 中 MTOR 的激活会破坏细胞生理稳态，导致睡眠/觉醒中断 为了检验这一假设，我们将生成细胞和小鼠 SKS 模型并进行研究。 致病性 SKS 变异如何影响 MTOR 活性、昼夜节律、睡眠/觉醒稳态以及 我们希望提供更好理解的原理证明。 超越基因型的因果机制使精准医学治疗策略成为可能。 抑制剂雷帕霉素会影响睡眠时间/阶段和质量，值得注意的是，低剂量雷帕霉素针对睡眠时间/阶段进行了优化。 特定等位基因使 MTOR 活性正常化，能够恢复患者的睡眠/觉醒模式，同时 我们将探索雷帕霉素治疗方案并检验以下假设： 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。 由于雷帕霉素会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型神经生理学生物标志物的概念 雷帕霉素剂量、MTOR 活性和 CNS 稳态这项研究将为未来奠定基础。 此外，这项研究对其他研究具有直接和更广泛的影响。 MTO 疾病，包括 TSC。