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.

不宁腿综合征（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%的成年人