Control of Alcohol Responses by Actin-Regulating Genes

肌动蛋白调节基因控制酒精反应

基本信息

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
项目类别：
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&apos 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

项目摘要

–––– 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，每年影响数百万人 AUD 的风险因素包括对酒精中毒作用的最初抵抗力，以及重复接触 AUD 后产生耐受性也有显着的遗传病因和许多基因。人类全基因组关联研究（GWAS）（包括我们的 A 研究）表明了这一点。然而，对其中许多基因的详细分子了解仍然缺乏。许多哺乳动物酒精转录组学研究都涉及“细胞骨架”，并且主要肌动蛋白动力学的调节因子包括 GTPases 的 Rho 家族及其调节因子，我们的研究结果得到了支持。通过此竞争性更新拨款的先前资助期，已表明 Rho GTPase 调节器中的 SNP RSU1 与酒精依赖性和饮酒相关，强调了我们的转化意义该补充应用程序有几个研究目标：i) 在 2 个科学目标中，Pearl Cummins 将实现以下目标：确定 Rac1 GTPase 调节剂 RhoGAP18B 在乙醇诱导的耐受性中的作用并研究正常酒精反应需要 RhoGAP18B 的神经递质系统在第二个目标中，Pearl 将会。确定果蝇是否可以作为模式生物来研究其机制第一个目标建立在父补助金的目标 1 的基础上，并结合了一些最近生成的内容。初步数据的重点是酒精引起的对乙醇镇静作用的耐受性，通过失正测定来测量，因为享乐耐受性，而不是对运动的耐受性。酒精的致残作用会导致持续饮酒量的增加，我们需要确定果蝇是否可以作为高通量生物体来测试基因对享乐的贡献因此，珀尔的第二个目标是完全新颖和创新的，但逻辑上是从家长补助金的首要问题 ii) 提供具有人类受试者工作背景的 Pearl。在她之前的研究期间，接受过模型中遗传、分子和行为方法的科学培训 iii) 为 Pearl 提供有利于她作为独立科学家职业发展的技能的导师；对于后两个目标，我们为Pearl制定了详细的计划，她的实验技术是什么？将学习哪些课程活动将扩展她的科学和职业技能发展定期会议。与主要导师以及她的科学多元化的指导团队将为吸取并确保珍珠科学发展的进步； iv) 通过整合丰富劳动力队伍；珀尔出身于贫困的低收入家庭，父母均没有学士学位，在犹他大学的科学界以及更广泛的加法界。