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: 10738062
• 负责人: Adrian Rothenfluh
• 金额: $ 3.8万
• 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/10738062
• 关键词: Actins; Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohols; Anhedonia; Anxiety; Bachelor' s Degree; Behavioral; Biological Assay; Brain; Chronic; Communities; Consumption; Cytoskeleton; Data; Dependence; Development; Disease; Drosophila genus; Education; Ensure; Ethanol; Extramural Activities; Family; Feedback; Funding; GTPase-Activating Proteins; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Goals; Grant; Guanine; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate Phosphohydrolases; Health; Health Hazards; Human; Human Genome; Individual; Intervention; Intoxication; Learning; Low income; Mammals; Measures; Mediating; Mentors; Molecular; Motor; Neurons; Neurosciences; Neurotransmitters; Organism; Parents; Persons; Pharmaceutical Preparations; Phenotype; Physical Dependence; Play; Populations at Risk; Professional Competence; Psychological reinforcement; Publishing; RSU1 gene; Regulation; Research; Resistance; Rewards; Risk Factors; Rodent; Role; Scientist; Sedation procedure; Seizures; Self Stimulation; Signal Transduction; Societies; Specificity; Substance abuse problem; Sucrose; System; Techniques; Testing; Therapeutic Intervention; Tissues; Training; United States; Universities; Utah; Vulnerable Populations; Withdrawal; Withdrawal Symptom; Writing; alcohol behavior; alcohol effect; alcohol exposure; alcohol response; alcohol sensitivity; alcohol use disorder; behavioral response; career development; driving force; dysphoria; experience; fly; genome wide association study; graduate student; hedonic; human subject; inhibitor; innovation; insight; meetings; member; model organism; negative emotional state; neural circuit; new therapeutic target; novel; parent grant; preference; problem drinker; programs; rho; rho GTP-Binding Proteins; satisfaction; skill acquisition; skills; symposium; therapy design; training opportunity; transcriptomics; willingness

–––– PROJECT SUMMARY / ABSTRACT FOR THE DIVERSITY SUPPLEMENT ––––––––––––––––––––––––––––– 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. There are several goals to this supplement application: i) in 2 scientific Aims, Pearl Cummins will determine the role of the Rac1 GTPase regulator RhoGAP18B in ethanol-induced tolerance and investigate the neurotransmitter systems that required RhoGAP18B for normal alcohol responses. In a second Aim, Pearl will determine whether Drosophila can be established as a model organism to investigate the mechanisms of hedonic tolerance. The first Aim builds on Aim1 of the parent grant and incorporates some recently generated preliminary data. The parent grant has a focus on alcohol-induced tolerance to the sedating effects of ethanol, as measured by a loss-of-righting assay. Since hedonic tolerance, rather than the tolerance to the motor- incapacitating effects of alcohol, contributes to the escalation of continued alcohol intake, we need to establish whether Drosophila can be used as a high-throughput organism to test the genetic contribution to hedonic tolerance. Thus, Pearl's second Aim is completely novel and innovative, but logically extends from the overarching question of the parent grant. ii) provide Pearl, who has a background in working with human subjects during her prior research, with scientific training on genetic, molecular, and behavioral approaches in model organisms. iii) Mentor Pearl in skills that are conducive to her career development as an independent scientist; For latter two goals, we have developed a detailed plan for Pearl in what the experimental techniques are she will learn and what curricular activities will expand her scientific and career skill development. Regular meeting with the primary mentor, as well as her scientifically diverse mentoring team will provide a trove of expertise to draw from, as well as ensure progress in Pearls scientific development; iv) enrich the workforce by integrating Pearl, who comes from an underprivileged low-income background with no parents holding a Bachelor's degree, in the scientific community here at the University of Utah, as well as the wider addition community.

-多样性补充的项目摘要/摘要 酒精滥用障碍(AUD)是一种主要的健康危害，每年影响美国数百万人 各州。AUD的风险因素包括对酒精醉人效应的初步抵抗力，以及 反复暴露时会产生耐受性。AUDS也有重要的遗传病因，许多基因 已经被人类全基因组关联研究所牵连，包括我们的研究。一个 然而，对这些基因中的许多基因的详细分子理解仍然缺乏。“肌动蛋白的调节 细胞骨架“已被大量哺乳动物酒精转录组学研究所牵连，而且主要 肌动蛋白动力学的调节者包括Rho家族的GTP酶及其调节者。我们的发现得到了支持 通过这项竞争性续签拨款的先前资金期限，已经表明Rho GTPase调节器中的SNPs RSU1与酒精依赖和饮酒有关，强调了我们的 学习。这个补充申请有几个目标：i)在两个科学目标中，珀尔·康明斯将 确定RhoGAP18B在乙醇诱导的耐受中的作用，并研究RhoGAP18B在乙醇诱导耐受中的作用 神经递质系统需要RhoGAP18B才能做出正常的酒精反应。在第二个目标中，珀尔将 确定果蝇是否可以作为模式生物来研究其作用机制 享乐主义容忍。第一个目标建立在父拨款的Aim1基础上，并结合了最近生成的一些 初步数据。父母拨款的重点是酒精诱导的对乙醇镇静作用的耐受性， 通过失正分析来衡量。因为享乐主义的容忍，而不是对马达的容忍- 酒精的致残作用，导致持续酒精摄入量的升级，我们需要确定 果蝇是否可以作为高通量生物来测试遗传对享乐主义的贡献 宽容。因此，珀尔的第二个目标是完全新颖和创新的，但在逻辑上是从 家长拨款的首要问题。二)提供珀尔，他有与人类受试者打交道的背景 在她之前的研究中，接受了关于遗传、分子和行为方法的科学培训 有机体。3)指导珀尔掌握有助于她作为独立科学家的职业发展的技能； 对于后两个目标，我们已经为珍珠制定了一个详细的计划，她的实验技术是什么 将学习和哪些课程活动将扩大她的科学和职业技能发展。例会 与主要导师，以及她的科学多样化的指导团队将提供宝贵的专业知识 借鉴并确保珍珠科学发展取得进展；四)通过整合丰富劳动力 珀尔来自贫困的低收入家庭，父母都没有学士学位。 在犹他大学的科学界，以及更广泛的加法社区。