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 经验影响，如应激性生活事件，与基因变异和 增加神经精神障碍的风险，如严重抑郁障碍(MDD)。 MDD困扰着大约6.7%的美国成年人，但MDD的治疗选择有限 而且效果不佳。这项提议的目标是定义全球表观遗传格局 与应激体验相关，并评估特定于基因座的表观遗传变化对 抑郁样表型的表现。我们建议首先揭露男性和 雌性小鼠对慢性不可预测的应激范式。然后我们将采取基因组方法 识别大脑中目标神经细胞类型的应激反应表观遗传密码。 最后，我们将修改和应用CRISPR/CAS9技术来处理因果关系 已识别的表观遗传密码与抑郁样行为的表达之间的关系。使用 目前可用的最先进技术和我们新开发的转基因 老鼠工具，我们希望洞察应激通过的表观遗传机制 与易感基因相互作用，增加MDD的风险。我们建议的研究将 还可以更好地了解与应激相关的神经精神障碍的潜在原因 并为改进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.