Understanding the Epigenetic Mechanisms Underlying Stress-related Neuropsychiatric Disorders

摘要 流行病学研究提供了越来越多的证据，支持环境和 经历的影响，例如压力性生活事件，与遗传变异相互作用， 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 与压力体验相关，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。我们建议首先暴露男性和 雌性小鼠慢性不可预测的压力模式。然后我们将采用基因组方法 以确定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，我们将修改并应用CRISPR/Cas9技术来解决因果关系。 在已识别的表观遗传密码与抑郁症样行为的表达之间。与 目前可用的最先进的技术和我们新开发的，转基因 我们希望能够深入了解压力通过表观遗传机制 与易感基因相互作用并增加MDD的风险。我们建议的研究将 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 疾病和为改善诊断和干预提供必要的基础。

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.