Neuroimmune interactions in Rett syndrome

雷特综合征的神经免疫相互作用

基本信息

批准号：
10205951
负责人：
Janine M LaSalle
金额：
$ 58.12万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-10 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10205951
关键词：
Acute Adolescent Adult Affect Age Age-Months Alleles Anxiety Body Weight Brain Brain Diseases Brain region Breathing Cells Cessation of life Chronic Cognitive Collection Complex Development Disease Disease Progression Dose Drug Targeting Drug usage Effectiveness Engineering Environment Environmental Risk Factor Epigenetic Process Event Exhibits Feces Female Future Gait Gene Mutation Genetic Genetic Risk Genotype Germ Lines Glutamates Heritability Hippocampus (Brain)Homeostasis Human Hypothalamic structure Immune Immune System Diseases Immune response Impairment Induced Mutation Inflammatory Injections Insulin-Like Growth Factor I Investigation Knock-in Knock-out Language Link Longevity Lung Measurement Measures Mediator of activation protein Mendelian disorder Metabolic Methyl-CpG-Binding Protein 2 Microglia Mitochondria Modeling Molecular Molecular Profiling Mosaicism Motor Motor Skills Mus Mutant Strains Mice Mutation Neurodevelopmental Disorder Neuroglia Neuroimmune Neurologic Neurologic Deficit Neurologic Symptoms Neuronal Dysfunction Neurons Onset of illness Organ Pathogenesis Patients Peripheral Phagocytosis Pharmaceutical Preparations Pharmacotherapy Phenotype Point Mutation Population Process Protein Isoforms Publishing Regulation Rest Rett Syndrome Role Schizophrenia Secondary to Sentinel Severities Severity of illness Shapes Speed Symptoms System Testing Time Tissue Banks X Chromosome X Inactivation autism spectrum disorder base body system causal variant cell injury cell type clinical investigation cytokine data modeling dietary control epigenome epigenomics excitatory neuron experience experimental study gait examination gastrointestinal function genome-wide girls gut microbiota immune activation improved in utero infancy inflammatory marker inhibitory neuron interest male metabolic phenotype metabolome microbiome microbiota metabolites microbiota profiles molecular dynamics molecular phenotype motor deficit motor symptom mouse model mutant neuronal circuitry novel postnatal pre-clinical receptor sex social anxiety synaptic pruning systemic inflammatory response therapeutic target transcriptome transcriptomics treatment group young adult

项目摘要

Neuroimmune interactions and epigenetic mechanisms act at the interface of genetic and environmental risk factors that determine the severity and progression of both common and rare brain disorders. A prime example of a complex monogenic disease is Rett syndrome, an X-linked dominant neurodevelopmental disorder caused by mutations in MECP2. Rett syndrome is epigenetic at two levels: first in the regulation of MECP2 by X chromosome inactivation, and second because MECP2 encodes a known epigenetic regulator, methyl CpG binding protein 2. Girls with Rett syndrome are heterozygous for MECP2 mutations that are primarily germ-line paternal de novo events. Rett babies are born apparently normal, and then experience a regression in cognitive and motor functions in late infancy. Mouse models of Rett syndrome also recapitulate the delay in the onset of detectable neurological symptoms and motor deficits. While the MeCP2 protein is most highly expressed in neurons, both human Rett patients and mouse models exhibit system-wide immune, mitochondrial, and metabolic manifestations that are likely secondary to the causal mutation’s disruption of neuronal homeostasis. What is lacking in the Rett field is a temporal understanding of how the molecular signatures of disease progression in distinct cell types within the brain interact with the immune system’s responses inside and outside of the brain. We propose to investigate the molecular signatures of critical time points of neuroimmune pathogenesis in a novel Rett syndrome mouse model based on a human mutation. Epigenomic investigation of specific cell types in cortex, including microglia, excitatory neurons, and inhibitory neurons will be integrated with 1) single cell transcriptomics from hippocampus and hypothalamus, 2) measurements of immune dysfunction, and 3) metabolite and gut microbiota profiles. The objective of the first aim will be to characterize the time course of neuroimmune interactions in the context of symptom progression in Rett syndrome. Results from the first aim will reveal the molecular dynamics of how immune responses exacerbate neuronal dysfunction and vice versa. In the second aim, we propose to modulate the microglia prior to the onset of disease progression to directly test the role of microglia in the timing and severity of symptoms in this Rett mouse model. LPS injections in pre-symptomatic mice will be performed to activate microglia so as to test the hypothesis that microglia activated by a “second hit” will increase the severity and speed of onset of neurologic and motor symptoms in the Rett syndrome model. As a reciprocal experiment, microglia will be depleted in adolescent mice using the drug PLX5622 and either allowed to replenish after short term drug treatment or continuously depleted through adulthood to test the hypothesis that microglia are critical mediators of symptom progression. From these experiments, we expect to obtain an integrated molecular time course of events explaining how Mecp2 mutation interacts with immune responses in brain and periphery. We will also determine if activated microglia in Rett syndrome may accelerate the disease severity and be an important therapeutic target for future pre-clinical investigations.

神经免疫相互作用和表观遗传机制作用于遗传和环境风险的界面决定常见和罕见脑部疾病的严重程度和进展的因素就是一个典型的例子。 Rett 综合征是一种复杂的单基因疾病，这是一种由 X 连锁显性神经发育障碍引起的疾病 MECP2 突变导致的 Rett 综合征在两个层面上具有表观遗传性：首先是 X 对 MECP2 的调节。染色体失活，其次是因为 MECP2 编码已知的表观遗传调节因子甲基 CpG 结合蛋白 2。患有 Rett 综合征的女孩的 MECP2 突变是杂合的，主要是种系突变父亲的新生事件，雷特婴儿出生时表面上是正常的，然后经历了退化。婴儿后期的认知和运动功能也重现了雷特综合征的延迟。出现可检测到的神经系统症状和运动缺陷，而 MeCP2 蛋白最为严重。在神经元中表达，人类 Rett 患者和小鼠模型都表现出全系统免疫，线粒体和代谢表现可能继发于因果突变的破坏 Rett 领域缺乏的是对分子如何实现神经元稳态的暂时理解。大脑内不同细胞类型的疾病进展特征与免疫系统相互作用我们建议研究关键时间的分子特征。基于人类突变的新型雷特综合征小鼠模型中神经免疫发病机制的要点。皮层特定细胞类型的表观基因组研究，包括小胶质细胞、兴奋性神经元和抑制性神经元神经元将与 1) 来自海马和下丘脑的单细胞转录组学整合，2) 免疫功能障碍的测量，以及 3) 代谢物和肠道微生物群概况第一个目标。目的是描述症状进展背景下神经免疫相互作用的时间过程第一个目标的结果将揭示免疫反应的分子动力学。加剧神经元功能障碍，反之亦然。在第二个目标中，我们建议先调节小胶质细胞。到疾病进展的开始，直接测试小胶质细胞在症状出现的时间和严重程度中的作用在这个 Rett 小鼠模型中，将对出现症状的小鼠进行 LPS 注射以激活小胶质细胞，从而检验这样的假设：“第二次打击”激活的小胶质细胞会增加疾病发作的严重程度和速度雷特综合征模型中的神经和运动症状作为交互实验，小胶质细胞将被研究。使用药物 PLX5622 在青春期小鼠中耗尽，并在短期药物后允许补充治疗或在成年后持续耗尽，以检验小胶质细胞至关重要的假设从这些实验中，我们期望获得整合的分子时间。事件的过程解释了 Mecp2 突变如何与大脑和外周免疫反应相互作用。还将确定雷特综合征中激活的小胶质细胞是否会加速疾病的严重程度并成为一种未来临床前研究的重要治疗靶点。