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.

项目概要/摘要 结节性硬化症（TSC）是一种相对常见的遗传性疾病，其特征是错构瘤 或肿瘤在包括大脑在内的多个器官中生长，并导致各种神经和神经精神疾病 症状，包括癫痫、智力障碍和自闭症。 TSC1 或 TSC2 基因突变会导致 雷帕霉素（mTOR）通路机械靶标的过度激活，可驱动肿瘤生长和 TSC 中的癫痫发生。高达 90% 的 TSC 患者会出现癫痫，并且在该地区很难治疗 大多数情况下，通常会导致终身致残的癫痫发作。睡眠障碍也是常见现象 TSC 是患者及其家人/护理人员生活质量下降的重要原因。 与 TSC 无关，癫痫和睡眠之间存在很强的关联，癫痫发作通常更频繁发生。 经常失眠，但人们对这种关系的机制基础知之甚少，并且两者之间存在联系 TSC 中的睡眠和癫痫发作尚未得到彻底研究。我们最近发现睡眠异常 TSC 小鼠模型（Tsc1GFAPCKO 小鼠）中的表型可能至少部分与 mTOR 依赖性相关 下丘脑食欲素表达增加。在此拨款提案中，我们建议调查 Tsc1GFAPCKO 小鼠癫痫和睡眠之间的现象学和机制关系，这也 进行性癫痫发作，以及另一种 TSC 小鼠模型和获得性癫痫模型。我们 假设 Tsc1GFAPCKO 小鼠的癫痫发作在睡眠中更常见。此外，我们假设 这些小鼠的癫痫至少部分是由 mTOR 依赖性下丘脑食欲素增加引起的 蛋白质翻译并对食欲素拮抗剂的治疗有反应。这项工作的创新之处在于 研究 TSC 中睡眠与癫痫发作之间的关系并确定下丘脑的潜在作用 食欲素在癫痫中的作用。这些研究的结果可能会对以下领域产生重大影响和转化应用： 开发治疗 TSC 癫痫的新疗法，特别是食欲素拮抗剂。由于 TSC 通常被视为 一般来说，癫痫和 mTORopathies 的模型遗传性疾病，该项目最终可能与 与其他原因有关的癫痫。