Control of Alcohol Responses by Actin-Regulating Genes

肌动蛋白调节基因控制酒精反应

• 批准号: 10306135
• 负责人: Adrian Rothenfluh
• 金额: $ 34.31万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10306135
• 关键词: ATAC-seq; Actins; Acute; Affect; Alcohol Phenotype; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohols; Anatomy; Animal Model; Antidotes; Area; Automobile Driving; Behavior; Behavior Control; Behavioral; Behavioral Mechanisms; Binding; Biological; Brain; Candidate Disease Gene; Cells; Chromatin; Chronic; Collaborations; Consumption; Cytoskeleton; DNA; Data; Dependence; Development; Disease; Drosophila genus; Elements; Engineering; Enhancers; Ethanol; Family; Feasibility Studies; Funding; GTPase-Activating Proteins; Gene Expression Regulation; Genes; Genetic; Genetic Predisposition to Disease; Genetic Transcription; Goals; Grant; Guanine; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate Phosphohydrolases; Health; Health Hazards; Human; Human Genome; Individual; Intervention; Link; Location; Measures; Mediating; Methods; Modeling; Molecular; Monomeric GTP-Binding Proteins; Motor; National Institute on Alcohol Abuse and Alcoholism; Neurons; Neurotransmitters; Nucleic Acid Regulatory Sequences; Orthologous Gene; Pathway interactions; Pharmaceutical Preparations; Phenotype; Promoter Regions; Protein Isoforms; Publications; Publishing; RSU1 gene; Regulation; Regulator Genes; Regulatory Element; Research; Research Personnel; Resistance; Rewards; Risk; Risk Factors; Role; Sedation procedure; Signal Transduction; Societies; Specificity; Substance abuse problem; System; Testing; Therapeutic Intervention; Tissue-Specific Gene Expression; Tissues; Transcriptional Regulation; Translational Research; United States; addiction; alcohol behavior; alcohol effect; alcohol exposure; alcohol response; alcohol sensitivity; alcohol use disorder; base; behavioral response; candidate validation; design; dopaminergic neuron; driving force; epigenome; experimental study; fly; gamma-Aminobutyric Acid; genetic approach; genome wide association study; improved; in vivo; inhibitor/antagonist; innovation; insight; interest; member; neural circuit; new therapeutic target; preference; relating to nervous system; response; rho; rho GTP-Binding Proteins; transcription factor; transcriptome; transcriptomics; translational approach; translational impact

Alcohol abuse disorders (AUD) are a major health hazard that affects millions of people every year in the United States. Risk factors for AUD include initial resistance to the intoxicating effects of alcohol, as well as the development of tolerance upon repeat exposure. AUDs also have significant genetic etiology, and many genes have been implicated from human genome-wide association studies (GWAS), including by our studies. A detailed molecular understanding of many of these genes is still lacking, though. “Regulation of the actin cytoskeleton” has been implicated by numerous mammalian alcohol transcriptomics studies, and major regulators of actin dynamics include the Rho family of GTPases, and their regulators. Our findings, supported by prior funding periods of this competitive renewal grant, have shown that SNPs in the Rho GTPase regulator RSU1 are associated with alcohol dependence and drinking, underscoring the translational significance of our studies. Our overall goal is to better understand the molecular mechanisms and neural tissue-specificity of Rho GTPase regulators using the powerful genetic toolkit of Drosophila. Based on our prior findings and extensive preliminary data, we hypothesize that different Rho GTPase regulators have distinct alcohol response phenotypes, depending on the neural circuits they are manipulated in. We will first determine the circuits and neurotransmitter systems that require regulators of the Rac1 GTPase from the Rho family for normal alcohol-induced sedation and tolerance. Second, we will determine the role in alcohol sedation and tolerance of 11 additional members of Rho GTPase signaling, including 8 orthologs of genes associated with addiction/alcohol phenotypes in human GWAS studies. These candidates have been suggested by alcohol- induced changes in accessibility of their DNA regulatory regions, as determined by our ATAC-seq experiments. The data also highlight four transcription factors, based on the overrepresentation of their binding motifs in alcohol-induced changes of accessible DNA regulatory elements. In a third aim, we will determine the role of two of these potential master regulators of alcohol-induced changes in gene regulation and in behavioral alcohol responses. The use of ATAC-seq to determine DNA regulatory elements in a tissue specific manner highlights a major innovative approach of our application. Taken together, these Aims are in line with NIAAA priorities focusing on the “Genetics of Alcohol Sensitivity and Tolerance”PA-18-660, which emphasize specific areas of research interest including “translational research in model organisms…for in vivo validation of candidate genes…from studies in humans”, and “studies of candidate genes…for tissue-specific gene expression, and for contributions to biological pathways”. Many prior publications linked to this grant, together with extensive preliminary data demonstrate the expertise of the investigator and the feasibility of the study. Our proven translational approach from Drosophila to humans will therefore have direct impact on the understanding of the function of human addiction genes.

酒精滥用障碍（AUD）是一种主要的健康危害，每年都会影响数百万人 美国。 AUD的危险因素包括对酒精的中毒作用的初始抵抗，以及 反复暴露时耐受性的发展。 AUDS还具有重要的遗传病因学，许多 基因已从人类全基因组关联研究（GWAS）实施，包括我们的研究。 但是，仍然缺乏对许多这些基因的详细分子理解。 “肌动蛋白的调节 众多哺乳动物酒精转录组学研究已经暗示了细胞骨架”，主要 肌动蛋白动态的调节器包括Rho的GTPases家族及其调节剂。我们的发现，得到了支持 通过此竞争性更新赠款的先前资助期，已表明Rho GTPase调节器中的SNP RSU1与酒精依赖和饮酒有关，强调了我们的翻译意义 研究。我们的总体目标是更好地了解分子机制和神经组织特异性 Rho GTPase调节剂使用果蝇强大的遗传工具包。根据我们先前的发现和 广泛的初步数据，我们假设不同的Rho GTPase调节剂具有独特的酒精 反应表型，具体取决于它们被操纵的神经回路。我们将首先确定 电路和神经递质系统，需要RAC1 GTPase的调节器Rho家族的调节器 正常酒精引起的镇静和耐受性。其次，我们将确定酒精镇静和 Rho GTPase信号的其他11个成员的公差，包括与与之相关的基因的8个直系同源 人类GWAS研究中的成瘾/酒精表型。这些候选人是由酒精提出的 由我们的ATAC-SEQ实验确定，诱导其DNA调节区域的可及性变化。 数据还强调了四个转录因子，基于其结合基序的过度代表 酒精引起的可访问的DNA调节元件的变化。在第三个目标中，我们将确定 这些潜在的主要调节剂中的两个酒精诱导的基因调节变化和行为变化 酒精反应。使用ATAC-SEQ以特定于组织的方式确定DNA调节元件 强调了我们应用的主要创新方法。综上所述，这些目标与NIAAA一致 重点关注“酒精敏感性和耐受性的遗传学” PA-18-660，强调特定 研究兴趣领域，包括“模型生物的转化研究……用于体内验证 候选基因……来自人类研究”和“候选基因的研究……组织特异性基因 表达，以及对生物途径的贡献”。许多先前与这项赠款相关的出版物 借助广泛的初步数据证明了研究者的专业知识和研究的可行性。 因此，我们从果蝇到人类的经过验证的翻译方法将直接影响 了解人类成瘾基因的功能。