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Understanding the Epigenetic Mechanisms Underlying Stress-Related Neuropsychiatric Disorders

了解压力相关神经精神疾病的表观遗传机制

基本信息

批准号：
9392597
负责人：
Zhaolan Zhou
金额：
$ 58.56万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-18 至 2018-01-17
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9392597
关键词：
Address Adult Affect Animals Behavior Behavioral Belief Biological Markers Brain CRISPR/Cas technology Catalytic Domain Characteristics Chimeric Proteins Clone Cells Code Communities DNA DNA Methylation DNA Sequence Alteration Development Diagnosis Diagnostic tests Disease Drug Targeting Epigenetic Process Etiology Event Exposure to Female Foundations Gene Expression Genes Genetic Genetic Variation Genome Genome engineering Genomic Segment Genomic approach Genomics Guide RNA Heritability Heterogeneity Human Intervention Life Link Major Depressive Disorder Mental Depression Mental disorders Modification Molecular Mus National Institute of Mental Health Neurons Nucleic Acid Regulatory Sequences Outcome Pathogenicity Pattern Phenotype Predisposition Prefrontal Cortex Reporting Research Risk Rodent Role Specificity Stress Susceptibility Gene Symptoms Technology Testing Transcript United States United States National Institutes of Health Woman behavioral outcome cell type clinical development coping depressive behavior design differential expression drug development epidemiology study epigenome epigenomics executive function experience experimental study hippocampal pyramidal neuron histone modification improved in vivo insight interest male markov model men neuropsychiatric disorder novel therapeutics response sex stable cell line tool

项目摘要

Title Understanding the Epigenetic Mechanisms Underlying Stress-related Neuropsychiatric Disorders Abstract Epidemiological studies provide mounting evidence supporting that environmental and experiential influences, such as stressful life events, interact with genetic variations and compound the risks for neuropsychiatric disorders, such as major depressive disorder (MDD). MDD afflicts about 6.7% of the United States adults, but treatment options for MDD are limited and not effective. The objective of this proposal is to define the global epigenetic landscape associated with stress experience and assess the effect of locus-specific epigenetic changes on the manifestation of depression-like phenotypes. We propose to first establish sex-specific stress paradigms to apply in male and female mice. We will then take a genomic approach to identify the stress responsive epigenetic code in targeted neuronal cell types in the brain. Finally, we will modify and apply CRISPR/Cas9 technology to address the causal relationship between the identified epigenetic code to the expression of depression-like behaviors. With currently available state-of-the-art technologies and our newly developed, genetically modified mouse tools, we hope to gain an insight into the epigenetic mechanisms through which stress interacts with susceptibility genes and confers increased risk to MDD. Our proposed study will also allow greater understanding of the underlying causes of stress-related neuropsychiatric disorders and provide the necessary foundation for improved diagnosis and intervention.

标题理解压力相关神经精神疾病的表观遗传机制障碍摘要流行病学研究提供了越来越多的证据，支持环境和经验的影响，如紧张的生活事件，与遗传变异和增加了神经精神疾病的风险，如重度抑郁症（MDD）。约6.7%的美国成年人患有MDD，但MDD的治疗选择有限而不是有效的。该提案的目的是定义全球表观遗传景观与压力经历相关，并评估基因座特异性表观遗传变化对抑郁症样表型的表现。我们建议首先建立性别特异性应激范例应用于雄性和雌性小鼠。然后我们将采用基因组方法来识别大脑中靶向神经元细胞类型中的应激反应表观遗传密码。最后我们将修改和应用CRISPR/Cas9技术，以解决确定了抑郁症样行为表达的表观遗传密码。与当前现有的最先进的技术和我们新开发的转基因小鼠工具，我们希望能够深入了解压力相互作用的表观遗传机制与易感基因，并赋予MDD的风险增加。我们提出的研究也将允许更深入地了解与压力有关的神经精神疾病的根本原因，为改进诊断和干预提供必要的基础。