Transcriptional Regulation of Alcohol Sensitivity and Tolerance

-项目摘要––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 对酒精最初的负面、醉人效应的抵抗力是酒精发展的一个危险因素。 使用无序。AUD的另一个特征和驱动因素是耐受性，这种耐受性是在反复暴露后形成的。是这样的 重复酒精暴露也会导致许多基因的表达变化，但许多基因转录 实施这些变化和调解容忍及其近亲依赖的机制仍有待于 已澄清。编码基因表达稳定变化的转录机制包括修饰 染色质。较少研究的染色质修饰机制之一是组蛋白甲基化，尤其是 组蛋白去甲基化酶(HDMS)。这个应用程序的目标是理解神经、分子、 以及KdM3HDM介导的初始敏感性和获得性耐受性调节的遗传机制 酒精。这是基于我们发表的研究结果，即果蝇敲除Kdm3基因会导致初始 敏感性，以及对重复酒精暴露的耐受性降低。首先，我们将确定神经元和 保守的神经递质系统，需要Kdm 3才能正常酒精反应。第二，我们将 测定酒精暴露引起的开放染色质中Kdm~3依赖的变化。这将包括一个 在乙醇诱导的改变区域有结合位点过度表达的转录因子分析 在染色质可及性方面。第三，我们将通过询问它们中的哪一个来研究可能的Kdm3靶基因 介导Kdm~3‘S对酒精诱导行为的影响。我们每个目标的前提都有以下支持 广泛的已公布和初步数据。总之，拟议的实验将阐明 Kdm~3介导的染色质修饰和基因调控，介导酒精敏感性和耐受性。 拟议的实验高度响应了NIAAA特别关注通知NOT-AA-21-029 “酒精敏感性和耐受性的遗传学”，并将提供“加强对遗传的理解， 基因组和表观遗传因素对个体敏感性和个体差异的生物学过程起作用 宽容的发展“(非-AA-21-029)。

––– PROJECT SUMMARY ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– Resistance to the initial negative, intoxicating effects of alcohol, is a risk factor in the development of alcohol use disorder. Another hallmark and driver of AUD is tolerance, which develops after repeat exposures. Such repeat alcohol exposures also lead to expression changes in numerous genes, yet many transcriptional mechanisms that enact these changes and mediate tolerance and its close relative, dependence, remain to be elucidated. Transcriptional mechanisms encoding stable changes in gene expression include the modification of chromatin. One of the lesser studied chromatin-modifying mechanisms is histone methylation, especially histone demethylating enzymes (HDMs). The goal of this application is to understand the neural, molecular, and genetic mechanisms of Kdm3 HDM-mediated regulation of initial sensitivity and of acquired tolerance to alcohol. This is based on our published findings that Drosophila knock out of Kdm3 causes increased initial sensitivity, and reduced tolerance to repeat ethanol exposure. First, we will determine the neurons and conserved neurotransmitter systems that require Kdm3 for normal alcohol responses. Second, we will determine Kdm3-dependent changes in open chromatin induced by alcohol exposure. This will include an analysis of transcription factors that have binding sites overrepresented in regions of ethanol-induced changes in chromatin accessibility. Third, we will investigate putative Kdm3-target genes by asking which of them mediate Kdm3’s effects on alcohol-induced behavior. The premise for each of our aims is supported by extensive published and preliminary data. Together, the proposed experiments will illuminate mechanisms of Kdm3-mediated chromatin modifications and gene regulation that mediate alcohol sensitivity and tolerance. The proposed experiments are highly responsive to the NIAAA Notice of Special Interest NOT-AA-21-029 “Genetics of Alcohol Sensitivity and Tolerance” and will provide an “enhanced understanding of genetic, genomic, and epigenetic factors contributing to biological processes for individual variation in sensitivity and the development of tolerance” (NOT-AA-21-029).