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

• 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
• 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

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.

不安的腿综合征（RLS）是一种与睡眠有关的感觉运动神经系统疾病，影响多达10％ 一般人口。 RLS的特征症状包括渴望患者经常移动双腿 伴随着或被认为是由腿部不舒服的感觉引起的。 RLS的病理生理是 不清楚。 RLS患者的全基因组关联研究（GWAS）已确定多达19个基因座 参与RLS。最重要的关联是MEIS1基因。 GWAS还将Meis1与 失眠，可能由RLS引起。此外，发现MEIS1与加速度计衍生有关 睡眠特征，包括睡眠持续时间，效率和时机。 MEIS1编码同型蛋白的蛋白质被认为是 转录因子。与RLS风险相关的Meis1内型单倍型与蛋白质降低有关 表达，表明这种变体会导致单倍不足。因此，杂合的Meis1淘汰赛（Meis1 KO）小鼠可以用作人RLS和其他睡眠障碍的潜在模型。我们已经测试了 Meis1 KO小鼠睡眠和其他类似RLS的表型。我们强大的初步数据表明Meis1 KO 小鼠过度活跃，醒来的可能性增加，尤其是在其余阶段。此外， MEIS1 KO小鼠的纹状体DA周转率增加，纹状体酪氨酸羟化酶和异常发射降低 纹状体胆碱能中间神经元。多巴胺能和纹状体胆碱能系统均已证明是 参与睡眠调节。但是，它们参与RLS和睡眠的潜在机制是 仍然不清楚。我们研究的广泛长期目标是使用MEIS1 KO小鼠了解 RLS，失眠和其他睡眠障碍的病理生理学，因此发展新型实验 治疗这些疾病的治疗剂。此应用的具体目标是确定 纹状体多巴胺能和胆碱能系统，用于RLS样表型和睡眠调节，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 单倍不足，它们对RLS样表型和睡眠调节的贡献有所不同。我们计划测试 我们的假设具有以下特定目的：1。检验多巴胺能系统的假设 为RLS和睡眠调节做出贡献，我们将创建多巴胺能特异性的MEIS1 KO小鼠和 进行全面的行为，生化，解剖学和电生理测试。 2。测试 纹状体胆碱能系统有助于RLS和睡眠调节的假设，我们将创建 胆碱能神经元特异性MEIS1 KO小鼠并在AIM 1中概述了全面的测试。 上述目标的完成将决定MEIS1单倍性影响多巴胺能 系统以及为什么可以使用多巴胺激动剂来治疗RLS。此外，该研究可以帮助改善 当前对RLS和其他睡眠障碍（包括失眠）的病理生理学的理解。这 结果可能有助于为患者提供新的治疗剂和更好的治疗策略的发展。