Promoting Resilience to Early Life Stress through Epigenetic Editing

通过表观遗传编辑提高对早期生活压力的抵抗力

基本信息

批准号：
10536990
负责人：
Rebekah Rashford
金额：
$ 3.08万
依托单位：
PRINCETON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10536990
关键词：
3-Dimensional Acute Adolescent Adopted Adult Animal Experimentation Anxiety Anxiety Disorders Architecture Automobile Driving Award Behavior Behavioral Bioinformatics Brain Cell Nucleus Cells Child Abuse and Neglect Childhood Chromatin Chromatin Structure Clinical Research Clustered Regularly Interspaced Short Palindromic Repeats Complex Computer Analysis DNA Data Data Analyses Development Enhancers Epigenetic Process Female Foundations Future Gene Expression Gene Expression Profile Genes Genetic Transcription Genome Genomics Glutamates Human Hypersensitivity In Vitro Label Life Link Longevity Measures Mediating Mental Depression Mental disorders Molecular Molecular Conformation Mood Disorders Mus Neurobiology Neurons Nuclear Envelope Nucleus Accumbens Parents Pathway interactions Poverty Predisposition Research Rewards Risk Risk Factors Sexual abuse Signal Transduction Stimulus Stress Sum System Testing Transcriptional Regulation Transgenic Mice Trauma Work XCL1 gene abuse neglect base behavioral response biological adaptation to stress brain cell career comparative disorder risk early experience early life stress emotional abuse epigenome epigenome editing experience experimental study genomic locus histone modification in vivo insight lifetime risk male mouse model neuropsychiatry physical abuse prevent relating to nervous system resilience response reward circuitry sex stressor three dimensional structure tool whole genome

项目摘要

PROJECT SUMMARY / ABSTRACT Early life stress (ELS) is one of the strongest predictors for development of mood and anxiety disorders. ELS can include trauma (neglect, and/or physical, sexual, and/or emotional abuse) or other negative childhood experiences. However, the increased risk for depression following ELS is not well understood. Previous work in a mouse model of stress across the lifespan has shown unique gene expression patterns after ELS and adult stress in the nucleus accumbens (NAc), a key region of the reward pathway implicated in stress response. The three-dimensional structure of chromatin is a key factor in determining how genes are regulated and expressed, with more open and accessible chromatin being permissive for gene expression and more closed chromatin repressing expression. We hypothesize that ELS changes chromatin accessibility within stress-responsive neuronal cells in the NAc such that the chromatin adopts a comparatively open conformation, making transcription more reactive to future stimuli. In Aim 1, I will determine how chromatin architecture is altered specifically within ELS-activated neurons using a double-transgenic mouse to label and capture both activated and non-activated neurons, then perform ATAC-sequencing and computational analyses to determine chromatin accessibility across the entire genome. I will examine how ELS alters chromatin structure in activated and non-activated cells in juvenile and adult mice of both sexes. In Aim 2, I will test the functional impact of chromatin state on transcriptional and behavioral susceptibility to adulthood stressors. First, I will apply CRISPR-dCas9-based epigenome editing tools to close chromatin at target genomic enhancer regions already identified in preliminary data to prevent hypersensitivity to activation in vitro. Then, I will use this tool in vivo to test the hypothesis that closing aberrantly open chromatin can reverse the impact of ELS and promote transcriptional and behavioral resilience. Together, this research will generate fundamental insights into how stress during key periods of development increases sensitivity to future stress at a molecular level in the brain.This project contributes to our understanding of the epigenetic mechanisms driving heightened risk of mood disorders following ELS.

项目摘要 /摘要早期生活压力（EL）是情绪和焦虑症发展的最强预测因素之一。 EL可以包括创伤（忽视和/或身体，性和/或情绪虐待）或其他负面的童年经验。但是，在ELS之后抑郁症的风险增加尚不清楚。以前的工作整个生命周期中应力的小鼠模型已显示出EL和成人后的独特基因表达模式伏隔核（NAC）的应力，奖励途径的关键区域与应力反应有关。这染色质的三维结构是确定基因如何调节和表达，更开放且可访问的染色质允许进行基因表达，并且更闭合染色质抑制表达。我们假设ELS改变了染色质的可及性 NAC中的应激响应性神经元细胞，使染色质采用相对开放的构象，使转录对未来的刺激更具反应性。在AIM 1中，我将确定染色质使用双转基因鼠标在ELS激活的神经元中特别改变架构，以标记和捕获激活和未激活的神经元，然后执行ATAC序列和计算分析确定整个基因组中的染色质可及性。我将研究ELS如何改变染色质两性的少年和成年小鼠活化和未激活的细胞中的结构。在AIM 2中，我将测试染色质状态对成年应激源的转录和行为敏感性的功能影响。首先，我将应用基于CRISPR-DCAS9的表观基因组编辑工具来关闭目标基因组的染色质增强子区域已经在初步数据中鉴定出来，以防止体外激活过敏。然后，我将使用此工具在体内测试以下假设：闭合闭合染色质可以逆转 ELS并促进转录和行为弹性。这项研究将共同产生基本深入了解开发关键时期的压力如何增加分子对未来压力的敏感性大脑中的水平。该项目有助于我们对驱动的表观遗传机制的理解 ELS之后的情绪障碍风险增加。