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).

——项目总结 –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––