Role of icarus in ethanol-induced behaviors

伊卡洛斯在乙醇诱导行为中的作用

• 批准号: 8538745
• 负责人: Shamsideen A Ojelade
• 金额: $ 2.95万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8538745
• 关键词: Adult; Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Behavior; Behavioral; Biochemical; Biological Assay; Brain; Cell Adhesion Molecules; Cells; Complementary DNA; Comprehension; Cysteine; Development; Disease; Dose; Drosophila genus; Drosophila melanogaster; Drug usage; Enhancers; Epidermal Growth Factor Receptor; Ethanol; Gene Expression; Genes; Genetic; Genetic Screening; Genetic screening method; Goals; Health Care Costs; Heritability; Human; Hyperactive behavior; Individual; Integrins; Malignant Neoplasms; Mediating; Molecular; Morbidity - disease rate; Motor Activity; Mutation; Neuraxis; Neurons; Oryctolagus cuniculus; Pathway interactions; Phenotype; Play; Productivity; RNA Interference; Research; Resistance; Risk Factors; Role; Sedation procedure; Signal Pathway; Signal Transduction; Signaling Molecule; Societies; Testing; Therapeutic; Tumor Suppressor Proteins; United States; Western Blotting; Work; absorption; addiction; alcohol behavior; alcohol effect; alcohol exposure; alcohol response; alcohol sensitivity; alcohol use disorder; disability; fly; histidine-rich proteins; improved; interest; mortality; mutant; novel; novel therapeutics; problem drinker; receptor; response

DESCRIPTION (provided by applicant): Alcohol is one of the most widely used drugs in the U.S. and long-term abuse is devastating to individuals and society. Unfortunately, few therapeutics are available to treat the effects of alcohol addiction and the molecular mechanisms causing long-term abuse are still unclear. To identify novel genes that regulate ethanol sensitivity, we conducted a genetic screen in Drosophila melanogaster and identified a mutation in the Ras suppressor 1 (Rsu1)-encoding icarus (ics) gene. Fly strains carrying a mutation in the ics gene are resistant to the activating and sedating effects of alcohol. In this proposal, I hypothesize that ics is required in the CNS to mediate alcohol-induced responses and works through the integrin and EGFR signaling pathways to exert its effect. In this proposal, I will test hypothesis using genetic, biochemical and behavioral approaches to elucidate the molecular role of ics in regulating alcohol-induced responses. In aim 1 I will determine whether ics is important in the adult central nervous system for normal alcohol responses. In aim 2, to determine whether ics exerts its effect through the integrin and EGFR/ERK pathways, I will test genetic interactions between ics and mutants in these receptors and their downstream signaling genes, and ask whether those mutations modify the ics ethanol- resistance. Lastly, to identify the neurocircuit in the fly brain affecting alcohol- induced behaviors, I will generate novel enhancer-Gal4 lines with specific expression in the fly brain, and assess if they affect alcohol responses. In addition, I will test whether inhibition of ics in these Gal4 lines affects alcohol hyperactivity or sedation using RNAi mediated knockdown. Findings from this proposal will improve our comprehension of the molecular mechanism(s) of alcohol behavioral responses and help to create better treatments for addiction.

描述（由申请人提供）：酒精是美国使用最广泛的药物之一，长期虐待对个人和社会造成了破坏。不幸的是，很少有治疗药物可用于治疗酒精成瘾的作用，导致长期滥用的分子机制仍不清楚。为了鉴定调节乙醇敏感性的新型基因，我们在果蝇中进行了遗传筛选，并鉴定了RAS抑制1（RSU1）编码ICARUS（ICS）基因中的突变。携带ICS基因突变的蝇菌株对酒精的激活和镇静作用有抵抗力。在此提案中，我假设中枢神经系统需要ICS介导酒精诱导的反应，并通过整合素和EGFR信号通路来发挥其作用。在此提案中，我将使用遗传，生化和行为方法检验假设，以阐明ICS在调节酒精诱导的反应中的分子作用。在AIM 1中，我将确定IC在成人中枢神经系统中是否对正常酒精反应很重要。在AIM 2中，为了确定IC是否通过整联蛋白和EGFR/ERK途径发挥其作用，我将测试这些受体中ICS与突变体之间的遗传相互作用及其下游信号基因，并询问这些突变是否改变了ICS乙醇抵抗。最后，为了确定影响酒精诱发行为的苍蝇大脑中的神经循环，我将产生新颖的增强剂 - gal4线，并在蝇脑中具有特定的表达，并评估它们是否影响酒精反应。此外，我将测试使用RNAi介导的敲低的抑制IC是否会影响酒精过快或镇静。该提案的发现将提高我们对酒精行为反应的分子机制的理解，并有助于为成瘾创造更好的治疗方法。