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: 10889349
• 负责人: Adrian Rothenfluh
• 金额: $ 6.08万
• 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/10889349
• 关键词: ATAC-seq; Actins; Acute; Affect; Alcohol Phenotype; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholic Intoxication; Alcohols; Anatomy; 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; Intoxication; 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; Persons; Pharmaceutical Preparations; Phenotype; Populations at Risk; Promoter Regions; Protein Isoforms; Publications; Publishing; RSU1 gene; Regulation; Regulator Genes; Regulatory Element; Research; Research Personnel; Resistance; Rewards; 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; behavioral response; candidate identification; candidate validation; dopaminergic neuron; driving force; epigenome; experimental study; fly; gamma-Aminobutyric Acid; genetic approach; genome wide association study; improved; in vivo; inhibitor; innovation; insight; interest; member; model organism; neural; neural circuit; new therapeutic target; preference; rational design; 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，每年影响数百万人， 美国的AUD的风险因素包括对酒精中毒作用的初始抵抗力，以及 对反复暴露的耐受性的发展。AUD也具有显著的遗传病因学，并且许多 人类全基因组关联研究（GWAS），包括我们的研究，已经涉及到基因。 然而，对许多这些基因的详细分子理解仍然缺乏。“肌动蛋白的调节 许多哺乳动物酒精转录组学研究都涉及到“细胞骨架”， 肌动蛋白动力学的调节剂包括GTP酶的Rho家族及其调节剂。我们的发现，支持 通过这种竞争性更新补助金的先前资助期，已经表明Rho GTdR调节器中的SNP RSU 1与酒精依赖和饮酒有关，强调了我们的翻译意义。 问题研究我们的总体目标是更好地了解神经细胞凋亡的分子机制和神经组织特异性。 使用果蝇强大的遗传工具包的Rho GT3调节剂。根据我们先前的发现， 根据广泛的初步数据，我们假设不同的Rho GT3调节剂具有不同的酒精浓度， 反应表型，这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，需要来自Rho家族的Rac 1 GTdR的调节剂， 正常的酒精诱导镇静和耐受性。其次，我们将确定酒精镇静作用， Rho GT3信号传导的11个额外成员的耐受性，包括与 在人类GWAS研究中的成瘾/酒精表型。这些候选人是由酒精推荐的- 诱导其DNA调控区可及性的变化，如我们的ATAC-seq实验所确定的。 这些数据还突出了四个转录因子，基于它们的结合基序的过度表达， 酒精诱导的DNA调控元件的变化。在第三个目标中，我们将确定 其中两个潜在的主调节器酒精诱导的基因调节和行为变化， 酒精反应。使用ATAC-seq以组织特异性方式确定DNA调控元件 突出了我们应用的一个主要创新方法。总的来说，这些目标符合NIAAA 重点是“酒精敏感性和耐受性的遗传学“PA-18-660，其中强调具体的 研究兴趣领域包括“模式生物的转化研究...... 候选基因.来自人类研究”和“候选基因的研究.用于组织特异性基因 表达，以及对生物途径的贡献”。许多先前的出版物与此赠款有关， 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，我们已经证明的从果蝇到人类的翻译方法将对人类的免疫系统产生直接影响。 了解人类成瘾基因的功能。

项目成果

The Neurotransmitters Involved in Drosophila Alcohol-Induced Behaviors.

• DOI: 10.3389/fnbeh.2020.607700
• 发表时间: 2020
• 期刊: Frontiers in behavioral neuroscience
• 影响因子: 3
• 作者: Chvilicek MM;Titos I;Rothenfluh A
• 通讯作者: Rothenfluh A

From single flies to many genes: Using Drosophila to explore the genetics of psychostimulant consumption.

从单只果蝇到许多基因：利用果蝇探索精神兴奋剂消费的遗传学。

• DOI: 10.1073/pnas.2109994118
• 发表时间: 2021
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Titos,Iris;Rothenfluh,Adrian
• 通讯作者: Rothenfluh,Adrian

Flying Together: Drosophila as a Tool to Understand the Genetics of Human Alcoholism.

• DOI: 10.3390/ijms21186649
• 发表时间: 2020-09-11
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Lathen DR;Merrill CB;Rothenfluh A
• 通讯作者: Rothenfluh A

The Use of Drosophila to Understand Psychostimulant Responses.

• DOI: 10.3390/biomedicines10010119
• 发表时间: 2022-01-06
• 期刊: Biomedicines
• 影响因子: 4.7
• 作者: Philyaw TJ;Rothenfluh A;Titos I
• 通讯作者: Titos I

Systematic discovery of Rab GTPases with synaptic functions in Drosophila.

• DOI: 10.1016/j.cub.2011.08.058
• 发表时间: 2011-10-25
• 期刊: CURRENT BIOLOGY
• 影响因子: 9.2
• 作者: Chan, Chih-Chiang;Scoggin, Shane;Wang, Dong;Cherry, Smita;Dembo, Todd;Greenberg, Ben;Jin, Eugene Jennifer;Kuey, Cansu;Lopez, Antonio;Mehta, Sunil Q.;Perkins, Theodore J.;Brankatschk, Marko;Rothenfluh, Adrian;Buszczak, Michael;Hiesinger, P. Robin
• 通讯作者: Hiesinger, P. Robin