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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：
10442446
负责人：
Janine M LaSalle
金额：
$ 56.55万
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10442446
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 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 brain dysfunction 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在遗传和环境风险的界面上起作用