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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

基本信息

批准号：
10552582
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10552582
关键词：
Adult Alleles Astrocytes Behavior Binding Birth Brain Cells Characteristics Coculture Techniques Communication Complex Data Dendritic Spines Dietary Supplementation Disease Exhibits Female Functional disorder Genes Genetic Genetic Transcription Goals Heterozygote Homeostasis Human In Vitro Knock-out Knockout Mice 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 Sorting 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 mosaic motor deficit mutant nervous system disorder neuronal cell body new therapeutic target novel therapeutics response restoration therapeutic target transcriptome

项目摘要

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.

项目总结/摘要 Rett综合征（RTT）是一种严重的X连锁进展性疾病，目前尚无有效的治疗方法。神经发育障碍（NDD）由转录调节因子MECP 2突变引起。所以该提案的总体目标是了解RTT的潜在病理生理学，并确定新的治疗这种毁灭性疾病的方法Mecp 2突变小鼠（雄性无效小鼠和雌性杂合小鼠）小鼠）表现出一系列的神经异常，这些神经异常概括了人类疾病，包括减少的神经元树突复杂性和索马大小，以及严重的运动缺陷。重要的是，选择性地重新表达 Mecp 2在成年小鼠中的研究表明，RTT症状可以部分逆转，这表明， MeCP 2下游靶标的稳态也可以逆转或减轻RTT症状。一种这样的潜在下游治疗靶标是NF-κB。我之前的研究表明 Mecp 2功能丧失的主要原因是Mecp 1的上调，导致NF-κB信号传导异常（Kishi* and MacDonald* 等人，Nature Communications 2016）。引人注目的是，在Mecp 2基因敲除雄性小鼠中遗传性降低NF-κB通路部分挽救了他们减少的皮层树突复杂性，并大大延长了他们正常缩短的寿命此外，我们的初步数据表明，膳食补充NF-κB抑制剂维生素维生素D（VitD）部分挽救雄性小鼠Mecp 2-null表型。有趣的是，维生素D缺乏症非常普遍，在RTT患者中，并且与多种其他NDD有关，包括自闭症谱系障碍（ASD）。因此，我们推测，通过饮食中补充维生素D，NF-κB信号的减弱，在RTT中的广泛治疗益处，以及潜在的具有重叠病理学的其他神经系统疾病。我们建议通过比较维生素D补充剂的体内治疗潜力来验证我们的假设，在雌性Mecp 2杂合子小鼠中NF-κB的遗传衰减（目的1），确定维生素D是否补充剂通过细胞自主或细胞非自主来拯救RTT皮质神经元表型机制（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的连接水平，再到行为。虽然维生素D补充剂可能虽然没有提供RTT的“治愈”，但来自这种简单的、具有成本效益的补充剂的任何表型改善将是非常令人兴奋的，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善的机制，这可能导致额外的新治疗靶点，用于RTT和其他病理重叠的神经系统疾病。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Vitamin D modulates cortical transcriptome and behavioral phenotypes in an Mecp2 heterozygous Rett syndrome mouse model.

DOI：
10.1016/j.nbd.2022.105636
发表时间：
2022-04
期刊：
Neurobiology of disease
影响因子：
6.1
作者：
Ribeiro MC;MacDonald JL
通讯作者：
MacDonald JL

Atypical Neocortical Development in the Cited2 Conditional Knockout Leads to Behavioral Deficits Associated with Neurodevelopmental Disorders.

引用2条件性基因敲除中的非典型新皮质发育导致与神经发育障碍相关的行为缺陷。

DOI：
10.1016/j.neuroscience.2020.12.009
发表时间：
2021
期刊：
Neuroscience
影响因子：
3.3
作者：
Wagner,NikolausR;MacDonald,JessicaL
通讯作者：
MacDonald,JessicaL

miR-409-3p represses Cited2 to refine neocortical layer V projection neuron identity.

DOI：
10.3389/fnins.2022.931333
发表时间：
2022
期刊：
FRONTIERS IN NEUROSCIENCE
影响因子：
4.3
作者：
Wagner, Nikolaus R.;Sinha, Ashis;Siththanandan, Verl;Kowalchuk, Angelica M.;MacDonald, Jessica L.;Tharin, Suzanne
通讯作者：
Tharin, Suzanne

Vitamin D Supplementation Rescues Aberrant NF-κB Pathway Activation and Partially Ameliorates Rett Syndrome Phenotypes in Mecp2 Mutant Mice.

补充维生素 D 可挽救 Mecp2 突变小鼠中异常的 NF-κB 通路激活并部分改善 Rett 综合征表型。

DOI：
10.1523/eneuro.0167-20.2020
发表时间：
2020
期刊：
eNeuro
影响因子：
3.4
作者：
Ribeiro,MayaraC;Moore,SethM;Kishi,Noriyuki;Macklis,JeffreyD;MacDonald,JessicaL
通讯作者：
MacDonald,JessicaL

Epigenetic regulation of nervous system development and function.

神经系统发育和功能的表观遗传调控。