Genetic and behavioral analysis of developmental ethanol exposure in Drosophila

果蝇发育期乙醇暴露的遗传和行为分析

• 批准号: 7826920
• 负责人: Kimberly Devon McClure
• 金额: $ 5.33万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7826920
• 关键词: Adult; Alcohol-Induced Disorders; Alcohols; Animal Model; Animals; Behavior Disorders; Behavioral; Behavioral Genetics; Birth; Candidate Disease Gene; Circadian Rhythms; Control Animal; Data; Development; Drosophila genus; Drosophila melanogaster; Eating; Embryo; Ethanol; Ethanol toxicity; Fetal Alcohol Exposure; Fetal Alcohol Syndrome; Food; Functional disorder; Genes; Genetic; Genetic Screening; Goals; Health; Learning; Memory impairment; Molecular; Motor; Mutation; Neuraxis; Prevalence; Proteins; Public Health; Research; Risk; Series; Sleep disturbances; Staging; System; Time; alcohol exposure; fly; immunocytochemistry; novel; prevent; research study

DESCRIPTION (provided by applicant): The goal of the proposed studies is to develop Drosophila melanogaster as an animal model to investigate fetal alcohol syndrome. Previous studies indicate that genetic factors can modulate the degree of alcohol teratogenic risk, yet the identification of specific genes that influence developmental ethanol toxicity has been elusive. The proposed research will both characterize the developmental, behavioral and neuroanatomical changes that occur upon developmental ethanol exposure in flies, and identify novel gene products that alter developmental ethanol toxicity. Preliminary data has shown that flies reared on 5% ethanol food are half as viable compared to control animals and significantly delayed in developmental time. In addition, ethanol-reared flies are more sensitive, as adults, to the locomotor-stimulant effects of vaporized ethanol, indicating that ethanol rearing causes permanent behavioral changes. To define the stage of ethanol-induced lethality and the critical time window of ethanol toxicity, a series of experiments will be performed rearing animals on 0% and 5% ethanol food during discrete developmental stages. Behavioral deficits commonly associated with fetal alcohol syndrome, such as learning and memory deficits, motor dysfunction, circadian rhythm deregulation, as well as eating and sleeping disturbances will be evaluated in both ethanol-reared and unexposed control adult flies. The behavioral disorders of fetal alcohol syndrome are thought to be caused by ethanol-induced injury to the developing central nervous system. Therefore, neuroanatomical damage and/or alterations following developmental ethanol exposure will be examined in both the embryonic and adult central nervous system using immunocytochemistry and the GAL4/UAS binary expression system, respectively. Finally, gene products that modify ethanol teratogenesis will be identified using both a candidate gene approach and an unbiased, forward genetic screen of single gene insertional mutations. Functional analysis of genes that modulate ethanol teratogenesis will be through a combination of molecular, behavioral and genetic approaches. Relevance to Public Health: The prevalence of fetal alcohol syndrome in the world is one to three per 1,000 births, indicating a serious health problem. Using the fruit fly to study the precise mechanisms of fetal alcohol syndrome has the potential to promote a better understanding of the actions of alcohol during development and to point the way to developing strategies that prevent (or mitigate) the damages of prenatal alcohol exposure.

描述（由申请方提供）：拟定研究的目的是开发黑腹果蝇作为研究胎儿酒精综合征的动物模型。先前的研究表明，遗传因素可以调节酒精致畸风险的程度，但影响发育乙醇毒性的特定基因的鉴定一直难以捉摸。拟议的研究将描述发育，行为和神经解剖学的变化，发生在发育乙醇暴露在苍蝇，并确定新的基因产物，改变发育乙醇毒性。初步数据显示，与对照动物相比，用5%乙醇食物饲养的果蝇存活率只有对照动物的一半，发育时间明显延迟。此外，乙醇饲养的苍蝇更敏感，作为成年人，蒸发乙醇的运动刺激作用，表明乙醇饲养引起永久性的行为变化。为了确定乙醇诱导致死性的阶段和乙醇毒性的关键时间窗，将在离散发育阶段用0%和5%乙醇饲料饲养动物进行一系列实验。将在乙醇饲养的和未暴露的对照成年果蝇中评价通常与胎儿酒精综合征相关的行为缺陷，如学习和记忆缺陷、运动功能障碍、昼夜节律失调以及进食和睡眠障碍。胎儿酒精综合征的行为障碍被认为是由酒精诱导的中枢神经系统发育损伤引起的。因此，神经解剖学损伤和/或发育乙醇暴露后的变化将在胚胎和成人中枢神经系统使用免疫细胞化学和GAL 4/UAS二元表达系统，分别检查。最后，将使用候选基因方法和单基因插入突变的无偏正向遗传筛选来鉴定修饰乙醇致畸作用的基因产物。调节乙醇致畸作用的基因的功能分析将通过分子，行为和遗传方法的组合。 与公共卫生的相关性：胎儿酒精综合症在世界上的流行率是每1 000名新生儿中有1至3名，这表明存在严重的健康问题。利用果蝇研究胎儿酒精综合征的确切机制，有可能促进更好地了解酒精在发育过程中的作用，并为制定预防（或减轻）产前酒精暴露损害的策略指明方向。