Transcriptional Regulation of Alcohol Sensitivity and Tolerance

酒精敏感性和耐受性的转录调控

• 批准号: 10651398
• 负责人: Adrian Rothenfluh
• 金额: $ 52.1万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651398
• 关键词: ATAC-seq; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohols; Amygdaloid structure; Anatomy; Behavioral; Binding; Binding Sites; Biological Assay; Biological Process; Brain; Chromatin; Chronic; Complex; Consumption; DNA; Data; Dependence; Development; Disease; Drosophila genus; Enhancers; Enzymes; Epigenetic Process; Ethanol; Ethanol dependence; Face; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genetic Variation; Genome engineering; Genomics; Goals; Histones; Human; Individual; Intoxication; Knock-out; Lysine; Mammals; Mediating; Methylation; Molecular; N-terminal; National Institute on Alcohol Abuse and Alcoholism; Neurons; Neurotransmitters; Orthologous Gene; Outcomes Research; Publishing; Regulation; Resistance; Risk Factors; Role; Sedation procedure; Surveys; System; Testing; Therapeutic Intervention; Tissues; Transcription Process; Transcriptional Regulation; Vulnerable Populations; alcohol behavior; alcohol effect; alcohol exposure; alcohol response; alcohol sensitivity; alcohol use disorder; chromatin modification; combinatorial; comparison control; demethylation; experimental study; fly; genetic approach; genetic manipulation; histone demethylase; histone methylation; histone modification; improved; individual variation; insight; interest; marijuana use; mutant; neural; neural circuit; neuroregulation; new therapeutic target; problem drinker; promoter; response; sedative; transcription factor; translation to humans; vinegar fly

––– 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).

––– 项目概要–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– 对酒精最初的负面、令人陶醉的影响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，这种耐受性是在重复接触后产生的。这样的 重复酒精暴露也会导致许多基因的表达变化，但许多转录 产生这些变化并调节耐受性及其近亲依赖性的机制仍有待研究。 阐明了。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（HDM）。该应用程序的目标是了解神经、分子、 以及 Kdm3 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研究结果，即果蝇敲除 Kdm3 会导致初始值增加 敏感性，并降低对重复乙醇暴露的耐受性。首先，我们将确定神经元和 需要 Kdm3 来进行正常酒精反应的保守神经递质系统。其次，我们将 确定酒精暴露引起的开放染色质中 Kdm3 依赖性变化。这将包括一个 分析在乙醇诱导的变化区域中具有过多结合位点的转录因子 染色质可及性。第三，我们将通过询问其中哪些基因来研究假定的 Kdm3 靶基因 介导 Kdm3 对酒精诱发行为的影响。我们每个目标的前提都得到支持 广泛的已发表数据和初步数据。总之，拟议的实验将阐明机制 Kdm3 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 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“对遗传、 基因组和表观遗传因素导致个体敏感性和生物过程的差异 耐受性的发展”（NOT-AA-21-029）。