Characterization of Meis1 mutant mice and implications in restless legs syndrome and other sleep disorders

Meis1 突变小鼠的特征及其对不宁腿综合征和其他睡眠障碍的影响

基本信息

批准号：
10267203
负责人：
YUQING LI
金额：
$ 19.06万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10267203
关键词：
Accelerometer Affect Anatomy Animal Model Behavioral Biochemical Cells Characteristics Code Core Facility Corpus striatum structure Data Development Disease Dopamine Dopamine Agonists Electrophysiology (science)Embryo Enhancers Environment Esthesia Family Florida Functional disorder Funding Ganglia General Population Goals Haplotypes Hardness Health Homeodomain Proteins Homeostasis Homologous Gene Human Hyperactivity Impairment Interneurons Investigational Therapies Iron Knock-out Knockout Mice Lead Leg Life Link MEIS1 gene Modeling Molecular Genetics Movement Mus Mutant Strains Mice Pathogenesis Patients Pharmaceutical Preparations Phenotype Polysomnography Population Prevalence Probability Proteins Research Research Personnel Research Project Grants Rest Resting Phase Restless Legs Syndrome Risk Role Running Serum Sleep Sleep Disorders Sleep disturbances Sleeplessness Substantia nigra structure Symptoms System Tail Techniques Testing Tyrosine 3-Monooxygenase United States National Institutes of Health Universities Variant Well in self Work Zebrafish behavior test cholinergic cholinergic neuron dopamine D3 receptor dopaminergic neuron falls genome wide association study improved interdisciplinary approach nervous system disorder neurodevelopment neurophysiology novel novel therapeutics protein expression risk variant sleep regulation therapy development trait transcription factor treatment strategy

项目摘要

Restless leg syndrome (RLS) is a sleep-related sensorimotor neurological disease affecting up to 10% of the general population. Characteristic symptoms of RLS include an urge for patients to move their legs often accompanied by, or felt to be caused by, uncomfortable sensations in the legs. The pathophysiology of RLS is unclear. Genome-wide association studies (GWAS) of RLS patients have identified up to 19 loci that are involved in RLS. The most significant association is within the MEIS1 gene. GWAS has also linked MEIS1 with insomnia, which can be caused by RLS. Besides, MEIS1 is found to be associated with accelerometer-derived sleep traits, including sleep duration, efficiency, and timing. MEIS1 codes for a homeobox protein thought to be a transcriptional factor. A MEIS1 intronic haplotype linked to RLS risk is associated with decreased protein expression, suggesting the variant causes haploinsufficiency. Therefore, heterozygous Meis1 knockout (Meis1 KO) mice can be used as a potential model for human RLS and other sleep disorders. We have tested the Meis1 KO mice for sleep and other RLS-like phenotypes. Our strong preliminary data showed that Meis1 KO mice were hyperactive and had an increased probability of waking especially during the rest phase. In addition, Meis1 KO mice had increased striatal DA turnover, decreased striatal tyrosine hydroxylase and abnormal firing of striatal cholinergic interneurons. Both dopaminergic and striatal cholinergic systems have been shown to be involved in sleep regulation. However, the underlying mechanisms of their involvement in RLS and sleep are still unclear. The broad, long-term objective of our research is to use the Meis1 KO mice to understand the pathophysiology of RLS, insomnia and other sleep disorders, and therefore to develop novel experimental therapeutics to treat these diseases. The specific goal of this application is to determine the contribution of the striatal dopaminergic and cholinergic systems to RLS-like phenotypes and sleep regulation, We hypothesize that the changes in dopaminergic and cholinergic systems are cell-autonomous effects of Meis1 haploinsufficiency and they contribute differently to RLS-like phenotypes and sleep regulation. We plan to test our hypothesis with the following Specific Aims: 1. To test the hypothesis that the dopaminergic system contributes to RLS and sleep regulation, we will create dopaminergic neuron-specific Meis1 KO mice and perform comprehensive behavioral, biochemical, anatomical, and electrophysiological tests. 2. To test the hypothesis that the striatal cholinergic system contributes to RLS and sleep regulation, we will create cholinergic neuron-specific Meis1 KO mice and perform comprehensive tests outlined in Aim 1. The successful completion of the above Aims will determine how MEIS1 haploinsufficiency influences the dopaminergic system and why dopamine agonists can be used to treat RLS. In addition, the study can help improve the current understanding of the pathophysiology of RLS and other sleep disorders, including insomnia. The results can potentially aid in the development of novel therapeutics and better treatment strategies for patients.

不宁腿综合症 (RLS) 是一种与睡眠相关的感觉运动神经系统疾病，影响高达 10% 的人一般人群。 RLS 的典型症状包括患者经常想要移动双腿伴随或感觉由腿部不适感引起。 RLS 的病理生理学是不清楚。 RLS 患者的全基因组关联研究 (GWAS) 已确定了多达 19 个基因座参与RLS。最显着的关联是在 MEIS1 基因内。 GWAS 还将 MEIS1 与失眠，这可能是由 RLS 引起的。此外，MEIS1被发现与加速度计衍生的睡眠特征，包括睡眠持续时间、效率和时间。 MEIS1 编码同源框蛋白，被认为是转录因子。与 RLS 风险相关的 MEIS1 内含子单倍型与蛋白质减少有关表达，表明该变异导致单倍体不足。因此，杂合 Meis1 敲除（Meis1 KO) 小鼠可用作人类 RLS 和其他睡眠障碍的潜在模型。我们已经测试了 Meis1 KO 小鼠的睡眠和其他 RLS 样表型。我们强有力的初步数据表明 Meis1 KO 小鼠过度活跃，醒来的可能性增加，尤其是在休息阶段。此外， Meis1 KO 小鼠纹状体 DA 周转增加、纹状体酪氨酸羟化酶减少和异常放电纹状体胆碱能中间神经元。多巴胺能系统和纹状体胆碱能系统均已被证明参与睡眠调节。然而，它们参与 RLS 和睡眠的根本机制是仍不清楚。我们研究的广泛、长期目标是使用 Meis1 KO 小鼠来了解 RLS、失眠和其他睡眠障碍的病理生理学，因此开发新的实验治疗这些疾病的疗法。该应用程序的具体目标是确定纹状体多巴胺能和胆碱能系统对 RLS 样表型和睡眠调节的影响，我们假设多巴胺能和胆碱能系统的变化是 Meis1 的细胞自主效应单倍体不足，并且它们对 RLS 样表型和睡眠调节的贡献不同。我们计划测试我们的假设具有以下具体目标： 1. 检验多巴胺能系统的假设有助于 RLS 和睡眠调节，我们将创建多巴胺能神经元特异性 Meis1 KO 小鼠，进行全面的行为、生化、解剖和电生理学测试。 2. 测试假设纹状体胆碱能系统有助于 RLS 和睡眠调节，我们将创建胆碱能神经元特异性 Meis1 KO 小鼠并进行目标 1 中概述的全面测试。完成上述目标将确定 MEIS1 单倍体不足如何影响多巴胺能系统以及为什么多巴胺激动剂可用于治疗 RLS。此外，该研究还可以帮助改善目前对 RLS 和其他睡眠障碍（包括失眠）的病理生理学的了解。这结果可能有助于开发新的疗法和更好的患者治疗策略。