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.

项目摘要/摘要 结节性硬化症复合物（TSC）是一种相对常见的遗传疾病，具有瘤瘤 或包括大脑在内的多个器官的肿瘤生长，并引起各种神经系统和神经精神病学 症状，包括癫痫，智力残疾和自闭症。 TSC1或TSC2基因的突变导致 雷帕霉素（MTOR）途径的机械靶标的过度激活，该途径驱动肿瘤生长和 TSC中的癫痫发生。癫痫发生在多达90％的TSC患者中，并且在治疗 大多数案件，通常导致终身残疾人癫痫发作。睡眠障碍也是常见的情况 在TSC中，患者和家庭成员/护理人员的生活质量降低了。 独立于TSC，癫痫和睡眠之间存在很强的关联，癫痫发作通常会产生更多 经常不睡觉，但是这种关系的机械基础知之甚少， 尚未对TSC的睡眠和癫痫发作进行彻底研究。我们最近发现睡眠异常 TSC（TSC1GFAPCKO小鼠）的小鼠模型中的表型，至少部分与MTOR依赖性有关 下丘脑OREXIN表达的增加。在这项赠款建议中，我们建议调查 TSC1GFAPCKO小鼠的癫痫与睡眠之间的现象学和机械关系，这也是 在TSC的另一个小鼠模型和获得的癫痫模型中具有渐进性癫痫发作。我们 假设癫痫发作更常见于TSC1GFAPCKO小鼠的睡眠中。此外，我们假设 这些小鼠中的癫痫至少部分是由于下丘脑Orexin的MTOR依赖性增加而引起的 蛋白质翻译，将对Orexin拮抗剂的治疗有反应。这项工作是创新的 调查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 癫痫病中的甲肌蛋白。这些研究的发现可能对 在TSC，尤其是Orexin拮抗剂中开发新的癫痫疗法。因为TSC经常被视为 对于癫痫和毛虫病的模型遗传疾病，该项目最终可能与 癫痫与其他原因有关。