Control of Alcohol Responses by Actin-Regulating Genes

- 项目概要/多样性评估摘要- 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。 States. AUD的风险因素包括对酒精中毒作用的初始抵抗力，以及 在重复暴露后产生耐受性。AUD也有显著的遗传病因学，许多基因 人类全基因组关联研究（GWAS），包括我们的研究都涉及到了这一点。一 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。 问题研究有几个目标，这一补充申请：i）在2个科学目标，珍珠康明斯将 确定Rac 1 GT3调节剂RhoGAP 18 B在乙醇诱导的耐受性中的作用，并研究Rac 1 GT3调节剂RhoGAP 18 B在乙醇诱导的耐受性中的作用。 神经递质系统需要RhoGAP 18 B来进行正常的酒精反应。在第二个目标中，珍珠将 确定果蝇是否可以作为模式生物来研究 享乐宽容第一个目标建立在母赠款的目标1的基础上，并结合了一些最近产生的 初步数据。家长补助金的重点是酒精诱导的耐受性的镇静作用的乙醇， 如通过翻正损失测定所测量的。因为享乐容忍度，而不是对运动的容忍度- 酒精的失能作用，有助于持续酒精摄入量的升级，我们需要建立 果蝇是否可以作为一个高通量的生物体来测试基因对享乐的贡献， 宽容因此，珀尔的第二个目标是完全新颖和创新的，但逻辑上是从 家长补助金的首要问题。ii）提供具有与人类受试者合作背景的Pearl 在她之前的研究中，她接受了遗传、分子和行为方法的科学培训， 有机体㈢指导Pearl掌握有助于其作为独立科学家职业发展的技能; 对于后两个目标，我们已经为Pearl制定了详细的计划，她的实验技术是什么 将学习什么课程活动将扩大她的科学和职业技能的发展。定期会晤 与主要导师，以及她的科学多样化的指导团队将提供一个专业知识宝库， 借鉴，以及确保珍珠科学发展的进步; iv）通过整合丰富劳动力 珀尔来自一个贫困的低收入家庭，父母都没有学士学位， 在犹他州的科学界，以及更广泛的加法界。

–––– 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.