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.

神经免疫性相互作用和表观遗传机制在遗传和环境风险的界面上作用决定常见和罕见脑部疾病的严重程度和进展的因素。一个很好的例子复杂的单基因疾病是Rett综合征，这是一种X连锁的显性神经发育疾病引起的通过MECP2中的突变。 RETT综合征在两个级别上表观遗传：首先是X调节MECP2 染色体灭活，其次是因为MECP2编码已知的表观遗传调节剂甲基CPG 结合蛋白2。患有RETT综合征的女孩对于主要种系的MECP2突变是杂合子 Patanal de Novo活动。 Rett婴儿天生显然是正常的，然后经历了回归婴儿期的认知和运动功能。 Rett综合征的鼠标模型还概括了可检测到的神经系统症状的发作和运动定义。而MECP2蛋白最高在神经元中表达的人类RETT患者和小鼠模型均表现出全系统免疫，线粒体和代谢表现可能是因果突变中断的继发的神经元体内平衡。 RETT领域缺少的是对分子如何的暂时理解大脑内不同细胞类型的疾病进展的特征与免疫系统相互作用大脑内外的反应。我们建议研究关键时间的分子特征基于人类突变的新型RETT综合征模型中神经免疫发病的点。皮质中特定细胞类型的表观基因组学研究，包括小胶质细胞，兴奋性神经元和抑制性神经元将与1）来自海马和下丘脑的单细胞转录组学集成，2）免疫功能障碍的测量以及3）代谢物和肠道菌群谱。第一个目的目的是表征症状进展的神经免疫相互作用的时间过程在Rett综合征中。第一个目标的结果将揭示免疫反应的分子动力学恶化神经元功能障碍，反之亦然。在第二个目标中，我们提议调整小胶质细胞疾病进展的发作，直接测试小胶质细胞在症状的时间和严重程度中的作用在此RETT鼠标模型中。将在症状前小鼠中注射LPS以激活小胶质细胞为了测试以下假设：“第二击”激活的小胶质细胞会增加 RETT综合征模型中的神经系统症状和运动症状。作为互惠实验，小胶质细胞将是使用药物PLX5622在青少年小鼠中耗尽，要么在短期药物后复制在成年期进行治疗或不断耗尽以检验小胶质细胞至关重要的假设症状进展的介体。从这些实验中，我们期望获得集成的分子时间事件的过程解释了MECP2突变如何与大脑和周围的免疫反应相互作用。我们还将确定RETT综合征中活化的小胶质细胞是否会加速疾病的严重程度，并且是未来临床前研究的重要治疗靶标。