Epigenetic priming of response to future stressors

对未来压力源反应的表观遗传启动

基本信息

批准号：
10609097
负责人：
Catherine Jensen Pena
金额：
$ 77.48万
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：
2022-04-12 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10609097
关键词：
3-Dimensional ATAC-seq Adult Anxiety Anxiety Disorders Award Behavior Behavioral Biological Brain Cell Nucleus Cells Child Chromatin Chromatin Structure Clinical Research Clustered Regularly Interspaced Short Palindromic Repeats Complex Computer Analysis Creativeness Cues DNA Structure Data Development Early identification Enhancers Epigenetic Process Failure Functional disorder Future Gene Expression Genes Genetic Risk Genetic Transcription Goals In Vitro Individual Intervention Lead Life Link Longevity Lysine Memory Mental Depression Mental Health Mental disorders Mission Modeling Molecular Mood Disorders Mus National Institute of Mental Health Neurobiology Outcome Process Recurrence Research Research Project Grants Rewards Risk Factors Role Scientist Shapes Site Specificity Stimulus Stress Stressful Event Suicide Testing Time Translating Ventral Tegmental Area Work behavioral response behavioral sensitization biobehavior cell type childhood adversity chromatin modification design early experience early life adversity epigenome epigenome editing experience experimental study genome-wide genomic locus high reward high risk histone modification in vitro testing in vivo innovation lifetime risk mouse model novel postnatal postnatal development preclinical study preservation programs promoter response social stress social stressor stressor three dimensional structure tool transcription factor transcriptomics

项目摘要

PROJECT SUMMARY Early life adversity (ELA) is one of the strongest lifetime risk factors for depression, anxiety, suicide, and other psychiatric disorders, particularly after facing additional stressful events later in life. ELA sensitizes individuals to future stressors and doubles the likelihood that a stressor in adulthood will result in an episode of depression or anxiety. However, the neurobiological basis of this stress sensitivity, or priming, remains almost entirely unexplored. Clinical and preclinical studies demonstrate a role for the ventral tegmental area (VTA) in ELA- attributable mood and anxiety disorders, and that ELA alters the course of VTA development and its function in response to both stressors and rewards. Using a mouse model to investigate the neurobiological impact of ELA, I previously found that ELA leads to lifelong transcriptomic changes in VTA including unique transcriptional response to adult stressors, which parallels latent behavioral changes we have observed. Gene expression is regulated by epigenetic mechanisms, and it was recently shown that the chromatin landscape continues to mature postnatally during a time when ELA has the greatest impact on stress sensitivity. Chromatin dynamically responds to developmental and environmental cues, acts as a substrate of molecular memory in cells, and facilitates adaptive gene expression response to recurring stimuli, a phenomenon termed epigenetic priming. In this Biobehavioral Research Awards for Innovative New Scientists (BRAINS) proposal, I will test the conceptually innovative hypothesis that ELA alters maturation of the chromatin landscape, priming chromatin in a cell-type- specific manner as a biological mechanism of heightened reactivity to future stimuli. In Aim 1 we will apply cutting- edge sequencing approaches and computational analyses to understand how the chromatin landscape matures across normal postnatal development with cellular specificity, how ELA alters these trajectories, and whether such changes are engaged in enhanced response to future stressors. In Aim 2 we will develop novel epigenome editing tools to prime targeted genomic locations, which we will test in vitro and apply in vivo to understand mechanisms of sensitivity to future stimuli. While our CRISPR/dCas9-based epigenome priming approach entails a degree of risky innovation, it is balanced by promising preliminary data and we provide alternative approaches that would mitigate failure of this high-risk high-reward experiment. The proposed research will identify the neuroepigenetic mechanisms through which developmental brain plasticity encodes adversity and confers sensitivity to future stressors. This proposal is directly relevant to the NIMH Strategic Goal to examine mental illness trajectories across the lifespan. Understanding how ELA alters the course of brain development at the level of the epigenome has the potential to transform our understanding of the neurodevelopmental origins of ELA-attributable mental illness and potential critical windows for intervention. The Advisory Council formed through this BRAINS Award will optimally support the ultimate goal of translating our findings into development of novel treatments to mitigate the impact of childhood adversity on adverse mental health outcomes.

项目概要早期生活逆境 (ELA) 是导致抑郁、焦虑、自杀和其他疾病的最严重的终生风险因素之一。精神疾病，特别是在以后的生活中面临额外的压力事件之后。 ELA 提高个人敏感性未来的压力源，并使成年后的压力源导致抑郁症发作的可能性加倍或焦虑。然而，这种压力敏感性或启动的神经生物学基础几乎完全保留未经探索。临床和临床前研究证明腹侧被盖区（VTA）在 ELA- 归因于情绪和焦虑障碍，并且 ELA 改变了 VTA 的发育过程及其在对压力源和奖励的反应。使用小鼠模型研究 ELA 的神经生物学影响，我之前发现 ELA 会导致 VTA 终生转录组变化，包括独特的转录对成人压力源的反应，这与我们观察到的潜在行为变化相似。基因表达量为受表观遗传机制调节，最近表明染色质景观继续出生后成熟期是 ELA 对应激敏感性影响最大的时期。染色质动态对发育和环境线索做出反应，充当细胞中分子记忆的基质，并且促进对重复刺激的适应性基因表达反应，这种现象称为表观遗传启动。在对于这个创新新科学家生物行为研究奖（BRAINS）提案，我将从概念上进行测试创新假设：ELA 改变染色质景观的成熟，启动细胞类型中的染色质作为对未来刺激高度反应的生物机制的特定方式。在目标 1 中，我们将应用切割- 边缘测序方法和计算分析，以了解染色质景观如何成熟具有细胞特异性的正常产后发育，ELA 如何改变这些轨迹，以及是否这些变化有助于增强对未来压力源的反应。在目标 2 中，我们将开发新的表观基因组编辑工具来启动目标基因组位置，我们将在体外进行测试并在体内应用以了解对未来刺激的敏感性机制。虽然我们基于 CRISPR/dCas9 的表观基因组启动方法需要一定程度的风险创新，通过有希望的初步数据来平衡，我们提供替代方法这将减少这个高风险高回报实验的失败。拟议的研究将确定神经表观遗传机制，通过该机制，发育性大脑可塑性编码逆境并赋予对未来压力源的敏感性。该提案与 NIMH 战略目标（检查精神状态）直接相关。整个生命周期的疾病轨迹。了解 ELA 如何改变大脑发育过程表观基因组水平有可能改变我们对神经发育起源的理解 ELA 归因的精神疾病和潜在的关键干预窗口。顾问委员会成立通过这个 BRAINS 奖将最好地支持将我们的发现转化为发展的最终目标减轻童年逆境对不良心理健康结果影响的新疗法。