Restoration of Homeostasis of Downstream Targets of MeCP2 as a Potential Therapeutic Avenue for Rett Syndrome

MeCP2 下游靶点稳态的恢复作为雷特综合征的潜在治疗途径

• 批准号: 10330377
• 负责人: Jessica L. MacDonald
• 金额: $ 32.81万
• 依托单位: SYRACUSE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10330377
• 关键词: Adult; Alleles; Astrocytes; Behavior; Birth; Brain; Cells; Characteristics; Coculture Techniques; Communication; Complex; Data; Dendritic Spines; Dietary Supplementation; Disease; Exhibits; Female; Functional disorder; Genes; Genetic; Genetic Transcription; Goals; Homeostasis; Human; In Vitro; Knock-out; Knockout Mice; Lead; Link; Longevity; Mediating; Methyl-CpG-Binding Protein 2; Modeling; Molecular; Mosaicism; Motor; Mus; Mutant Strains Mice; Mutation; Nature; Neurodevelopmental Disorder; Neurologic; Neurons; Pathology; Pathway interactions; Patients; Phenotype; Quality of life; Rett Syndrome; Signal Pathway; Signal Transduction; Symptoms; Testing; Therapeutic; Up-Regulation; Variant; Vitamin D; Vitamin D Deficiency; Vitamin D supplementation; Vitamin D3 Receptor; Work; attenuation; autism spectrum disorder; behavioral phenotyping; boys; brain circuitry; cellular targeting; cost effective; dietary supplements; effective therapy; experimental study; girls; improved; in vivo; inhibitor; loss of function; male; motor deficit; mutant; nervous system disorder; neuronal cell body; new therapeutic target; novel therapeutics; response; restoration; therapeutic target; transcriptome

PROJECT SUMMARY / ABSTRACT There is currently no effective treatment for Rett syndrome (RTT), a severe X-linked progressive neurodevelopmental disorder (NDD) caused by mutations in the transcriptional regulator MECP2. Hence, the overall goal of this proposal is to understand the underlying pathophysiology of RTT, and identify novel therapeutic avenues for this devastating disorder. Mecp2 mutant mice (male null mice, and female heterozygous mice) exhibit a range of neurological abnormalities that recapitulate the human disorder, including reduced neuronal dendritic complexity and soma size, and severe motor deficits. Importantly, selectively re-expressing Mecp2 in adult mice has shown that RTT symptoms can be partially reversed, suggesting that restoration of homeostasis of downstream targets of MeCP2 could also reverse or alleviate RTT symptoms. One such potential downstream therapeutic target is NF-κB. My previous work demonstrated that a consequence of Mecp2 loss of function is up-regulation of Irak1, leading to aberrant NF-κB signaling (Kishi* and MacDonald* et al, Nature Communications 2016). Strikingly, genetically reducing the NF-κB pathway in Mecp2-null male mice partially rescues their reduced cortical dendritic complexity and substantially extends their normally shortened lifespan. Further, our preliminary data demonstrate that dietary supplementation with the NF-κB inhibitor vitamin D (VitD) partially rescues Mecp2-null phenotypes in male mice. Intriguingly, VitD deficiency is highly prevalent in RTT patients, and has been implicated in multiple other NDDs, including autism spectrum disorders (ASD). We thus hypothesize that attenuation of NF-κB signaling, via dietary supplementation with VitD, could have broad therapeutic benefit in RTT, and potentially other neurological disorders with overlapping pathology. We propose to test our hypotheses by comparing the in vivo therapeutic potential of VitD supplementation and genetic attenuation of NF-κB in female Mecp2 heterozygous mice (Aim 1), determining whether vitamin D supplementation rescues RTT cortical neuronal phenotypes via cell autonomous or cell-non-autonomous mechanisms (Aim 2), and determining underlying molecular mechanisms of this phenotypic rescue (Aim 3). We will take a unique, integrative approach, investigating phenotypic rescue from the molecular (transcriptome) and cellular level, to the level of neuronal and dendritic connectivity, to behavior. Although VitD supplementation may not provide a “cure” for RTT, any phenotypic improvement from such a simple, cost-effective supplement would be extremely exciting, with the potential for quality of life improvements. Further, we will identify molecular mechanisms underpinning the phenotypic improvements, which could lead to additional new therapeutic targets, for RTT and other neurological disorders with overlapping pathology.

项目摘要/摘要 目前还没有有效的治疗Rett综合征(RTT)的方法，RTT是一种严重的X连锁进行性疾病 由转录调控基因MECP2突变引起的神经发育障碍。因此， 这项建议的总体目标是了解RTT的潜在病理生理学，并确定新的 治疗这种毁灭性疾病的途径。MeCP2突变小鼠(雄性空白小鼠，雌性杂合子小鼠 小鼠)表现出一系列神经异常，概括了人类的疾病，包括减少 神经元树突的复杂性和胞体大小，以及严重的运动障碍。重要的是，选择性地重新表达 在成年小鼠身上的MeCP2已经表明RTT症状可以部分逆转，这表明 MeCP2下游靶点的动态平衡也可以逆转或缓解RTT症状。 其中一个潜在的下游治疗靶点是核因子-κB。我之前的研究表明， MeCP2功能丧失的一个原因是IRAK1上调，导致NF-κB信号异常(Kishi*和MacDonald* 等人，《自然通讯2016》)。引人注目的是，在基因上降低了κ基因缺失雄性小鼠的核因子-MeCP2 B途径 部分挽救了降低的皮质树突状细胞的复杂性，并显著延长了正常缩短的 寿命。此外，我们的初步数据表明，膳食中补充核因子-κB抑制剂维生素 D(VitD)部分挽救雄性小鼠MeCP2缺失表型。有趣的是，维生素D缺乏症非常普遍 在RTT患者中，并已与其他多种NDD有关，包括自闭症谱系障碍(ASD)。 因此，我们假设，通过膳食补充维生素D而减弱的NF-κB信号可能具有 RTT的广泛治疗益处，以及潜在的具有重叠病理的其他神经疾病。 我们建议通过比较补充维生素D和维生素D的体内治疗潜力来检验我们的假设 雌性κ杂合子小鼠中核因子-MeCP2 B的遗传衰减(目标1)，确定维生素D 补充剂通过细胞自主或细胞非自主拯救RTT皮层神经元表型 机制(目标2)，并确定这种表型拯救的潜在分子机制(目标3)。我们 将采取一种独特的、综合的方法，从分子(转录组)和 从细胞水平，到神经元和树突连接的水平，到行为。尽管维生素D补充剂可能 不能提供RTT的“治愈”，从这种简单、成本效益高的补充剂中进行的任何表型改进都将 非常令人兴奋，具有改善生活质量的潜力。此外，我们将鉴定分子 支持表型改进的机制，这可能导致更多新的治疗靶点， 用于RTT和其他具有重叠病理的神经疾病。