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：
10196918
负责人：
Zhaolan Zhou
金额：
$ 54.65万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2018-01-18 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10196918
关键词：
Address Adult Affect Animals Behavior Behavioral Belief Biological Markers Brain CRISPR/Cas technology Cell Line Characteristics Chronic 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 Transcription Genetic Variation Genome Genome engineering Genomic Segment Genomic approach Guide RNA Heritability Heterogeneity Human Intervention Laboratories 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 Model Role Specificity Stress Stressful Event Susceptibility Gene Techniques Technology Testing United States United States National Institutes of Health behavioral outcome cell type clinical development depressive behavior disorder risk drug development epidemiology study epigenome epigenome editing epigenomics executive function experience experimental study genomic locus hippocampal pyramidal neuron histone modification improved in vivo insight interest male markov model mouse model neuropsychiatric disorder neuropsychiatry novel therapeutics response tool

项目摘要

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 expose both male and female mice to chronic unpredictable stress paradigms. 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.

抽象的流行病学研究提供了越来越多的证据支持环境和经验影响，例如压力生活事件，与遗传变异相互作用，加剧神经精神疾病的风险，例如重度抑郁症（MDD）。约 6.7% 的美国成年人患有 MDD，但 MDD 的治疗选择有限并且没有效果。该提案的目标是定义全球表观遗传景观与压力经历相关并评估位点特异性表观遗传变化的影响抑郁症样表型的表现。我们建议首先暴露男性和雌性小鼠长期不可预测的压力范式。然后我们将采用基因组方法识别大脑中目标神经元细胞类型的应激反应表观遗传密码。最后，我们将修改并应用CRISPR/Cas9技术来解决因果关系已识别的表观遗传密码与抑郁症样行为的表达之间的关系。和目前可用的最先进技术和我们新开发的转基因技术小鼠工具，我们希望深入了解压力的表观遗传机制与易感基因相互作用，增加患 MDD 的风险。我们提出的研究将还可以更好地了解与压力相关的神经精神疾病的根本原因疾病并为改进诊断和干预提供必要的基础。