Interaction of Epilepsy and Sleep Disorders in a Mouse Model of Tuberous Sclerosis Complex

结节性硬化症小鼠模型中癫痫和睡眠障碍的相互作用

• 批准号: 10260074
• 负责人: MICHAEL WONG
• 金额: $ 39.38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10260074
• 关键词: Affect; Applications Grants; Arousal; Behavioral; Biochemical; Biological Assay; Brain; Caregivers; Data; Dependence; Development; Early treatment; Electroencephalography; Epilepsy; Epileptogenesis; FRAP1 gene; Family member; Frequencies; General Population; Genetic; Genetic Diseases; Genetic Models; Genetic Transcription; Grant; Hamartoma; High Prevalence; Hypothalamic structure; Injury; Intellectual functioning disability; Late Effects; Life; Link; Mediating; Methods; Modeling; Monitor; Morbidity - disease rate; Mus; Mutation; Neurologic; Neurologic Symptoms; Neuropeptides; Neurotransmitter Receptor; Organ; Pathologic; Pathway interactions; Patients; Phenotype; Population Research; Proteins; Public Health; Quality of life; Research; Role; Seizures; Sleep; Sleep Disorders; Sleep Stages; Sleep Wake Cycle; Sleeplessness; Source; Status Epilepticus; TSC1 gene; TSC2 gene; Testing; Therapeutic; Translations; Tuberous sclerosis protein complex; Western Blotting; Work; autism spectrum disorder; hypocretin; improved; innovation; kainate; mortality; mouse model; neuropsychiatric symptom; neuropsychiatry; non rapid eye movement; novel therapeutic intervention; novel therapeutics; orexin A; prevent; public health relevance; receptor; sleep abnormalities; tumor growth; vigilance

PROJECT SUMMARY/ABSTRACT Tuberous sclerosis complex (TSC) is a relatively common genetic disorder, which features hamartoma or tumor growth in multiple organs, including the brain, and causes a variety of neurological and neuropsychiatric symptoms, including epilepsy, intellectual disability, and autism. Mutation of the TSC1 or TSC2 genes leads to hyperactivation of the mechanistic target of rapamycin (mTOR) pathway, which drives tumor growth and epileptogenesis in TSC. Epilepsy occurs in up to 90% of TSC patients and is intractable to treatment in the majority of cases, often leading to life-long disabling seizures. Sleep disorders are also a common occurrence in TSC and a significant source of decreased quality of life for the patient and family members/caregivers. Independent of TSC, there is a strong association between epilepsy and sleep, with seizures often arising more frequently out of sleep, but the mechanistic basis for this relationship is poorly understood and a link between sleep and seizures in TSC has not been thoroughly investigated. We have recently identified an abnormal sleep phenotype in a mouse model of TSC (Tsc1GFAPCKO mice) that may at least in part relate to an mTOR-dependent increase in hypothalamic orexin expression. In this grant proposal, we propose to investigate the phenomenological and mechanistic relationship between epilepsy and sleep in Tsc1GFAPCKO mice, which also have progressive seizures, as well as in another mouse model of TSC and an acquired epilepsy model. We hypothesize that seizures occur more commonly in sleep in Tsc1GFAPCKO mice. Furthermore, we hypothesize that epilepsy in these mice are at least partly caused by an mTOR-dependent increase in hypothalamic orexin protein translation and will be responsive to treatment with an orexin antagonist. This work is innovative in investigating the relationship between sleep and seizures in TSC and identifying a potential role of hypothalamic orexin in epilepsy. The findings from these studies may have strong impact and translational applications for developing novel therapies for epilepsy in TSC, in particular orexin antagonists. As TSC is often viewed as a model genetic disorder for epilepsy and mTORopathies in general, this project may ultimately have relevance to epilepsy related to other causes.

项目总结/摘要 多发性硬化症是一种较为常见的遗传性疾病，以错构瘤为特征 或肿瘤生长在多个器官，包括大脑，并导致各种神经和神经精神疾病 症状，包括癫痫，智力残疾和自闭症。TSC 1或TSC 2基因的突变导致 雷帕霉素（mTOR）途径的机制靶点的超活化，其驱动肿瘤生长， TSC中的癫痫发生。癫痫发生在高达90%的TSC患者中，并且在TSC患者中难以治疗。 大多数情况下，往往导致终身致残癫痫发作。睡眠障碍也是一种常见的现象 TSC和患者和家庭成员/护理人员生活质量下降的重要来源。 独立于TSC，癫痫和睡眠之间有很强的联系，癫痫发作往往发生得更多， 经常失眠，但这种关系的机制基础知之甚少， TSC中的睡眠和癫痫发作尚未得到彻底研究。我们最近发现了一种异常睡眠 TSC小鼠模型（Tsc 1GFAPCKO小鼠）中的表型，其可能至少部分与mTOR依赖性 下丘脑食欲素表达增加。在这份拨款申请中，我们建议调查 Tsc 1GFAPCKO小鼠癫痫和睡眠之间的现象学和机制关系， 具有进行性癫痫发作，以及在另一种TSC小鼠模型和获得性癫痫模型中。我们 假设癫痫发作在Tsc 1GFAPCKO小鼠睡眠中更常见。此外，我们假设 这些小鼠的癫痫至少部分是由下丘脑食欲素mTOR依赖性增加引起的， 蛋白质翻译，并且将对用食欲素拮抗剂的治疗有反应。这项工作具有创新性， 研究TSC中睡眠和癫痫发作之间的关系，并确定下丘脑的潜在作用 食欲素治疗癫痫这些研究的结果可能对以下方面产生强烈的影响和转化应用： 开发用于TSC中癫痫的新疗法，特别是食欲素拮抗剂。由于TSC通常被视为 模型遗传性疾病的癫痫和mTORopathies一般，这个项目可能最终有相关性， 癫痫与其他原因有关