The Epigenome in Substance Abuse Disorders: Engineering New Tools to Dissect Function from Form

药物滥用疾病中的表观基因组：设计新工具从形式中剖析功能

基本信息

批准号：
9761510
负责人：
Albert Keung
金额：
$ 45.6万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2022-08-31
项目状态：
已结题

项目摘要

Many studies have connected epigenomic changes to substance abuse disorders. However, there is a key barrier to our understanding of the epigenome’s mechanistic roles. While epigenomic modifications have been widely mapped and correlated with changes in gene expression and cellular phenotypes, correlation does not demonstrate function or causation. This barrier arises because widely used techniques to perturb the epigenome, including pharmacological inhibition and genetic knock-outs or overexpressions, suffer from pleiotropic effects. Thus, it is unclear if epigenomic modifications drive, are a result of, or are simply associated with changes in gene states. Two important corollaries arise from this: 1) It is unclear whether and which epigenome modifications drive changes in gene expression, and 2) the temporal stability of epigenome modifications that would result in truly persistent “epigenetic” properties is unknown. The hypothesis of the proposed work is that the epigenome represents a powerful regulatory system layered on top of the genome, and by engineering new tools to interface with and control this system, we can harness its unique properties to understand and tackle substance abuse disorders. A guiding goal is to dissect the function of epigenome modifications from their form and demonstrate their specific relevance to substance abuse disorders. To achieve this, we will develop tools to sense and induce changes in the epigenome, and do so spatiotemporally in systems reflective of human genetics, epigenetics, and physiology.

许多研究已将表观基因组变化与药物滥用疾病联系起来。我们理解表观基因组的机制作用的关键障碍。修饰已被广泛绘制并与基因表达和细胞的变化相关表型、相关性并不能证明功能或因果关系。这种障碍的出现是因为。广泛使用的扰乱表观基因组的技术，包括药理抑制和遗传敲除或过度表达会受到多效性影响，因此，尚不清楚表观基因组是否存在。修饰驱动基因状态的变化，是基因状态变化的结果，或者仅仅与基因状态的变化相关。由此产生了重要的推论：1）尚不清楚是否以及哪些表观基因组修饰驱动基因表达的变化，2）表观基因组修饰的时间稳定性是否会导致真正持久的“表观遗传”特性尚不清楚。工作是表观基因组代表了一个位于基因组之上的强大的调控系统，通过设计新的工具来连接和控制这个系统，我们可以利用它理解和解决药物滥用障碍的独特属性的一个指导目标是剖析。从其形式观察表观基因组修饰的功能并证明其与为了实现这一目标，我们将开发工具来感知和诱导药物滥用疾病的变化。表观基因组，并在反映人类遗传学、表观遗传学和生理。