Transcriptional Regulation of Alcohol Sensitivity and Tolerance

- 项目概要- 对酒精最初的负面、致醉作用的抵抗力是酒精发展的一个危险因素 使用障碍。AUD的另一个标志和驱动因素是耐受性，它在重复暴露后发展。等 重复的酒精暴露也会导致许多基因的表达变化，但许多转录 制定这些变化和调节耐受性及其近亲依赖性的机制仍有待研究。 阐明。编码基因表达稳定变化的转录机制包括修饰 染色质。研究较少的染色质修饰机制之一是组蛋白甲基化，特别是 组蛋白去甲基化酶（HDMs）。这个应用程序的目标是了解神经，分子， Kdm 3 HDM介导的初始敏感性和获得性耐受调节的遗传机制 酒精这是基于我们发表的发现，即敲除Kdm 3的果蝇引起初始 敏感性和对重复乙醇暴露的耐受性降低。首先，我们将确定神经元， 保守的神经递质系统需要Kdm 3来进行正常的酒精反应。二是 确定酒精暴露诱导的开放染色质中的Kdm 3依赖性变化。这将包括 分析在乙醇诱导的变化区域中具有过量结合位点的转录因子 染色质可及性。第三，我们将调查推定的Kdm 3靶基因，通过询问它们中的哪一个， 介导Kdm 3对酒精诱导行为的影响。我们每一个目标的前提都得到了以下方面的支持： 广泛的已发表和初步数据。总之，拟议的实验将阐明机制， kdm 3介导的染色质修饰和基因调控介导的酒精敏感性和耐受性。 建议的实验对NIAAA特别关注通知NOT-AA-21-029具有高度响应性 “酒精敏感性和耐受性的遗传学”，并将提供“增强对遗传， 基因组和表观遗传因素有助于敏感性个体差异的生物过程， 耐受性的形成”（NOT-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).