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: 7625073
• 负责人: Kimberly Devon McClure
• 金额: $ 5.01万
• 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/7625073
• 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(申请人提供)：拟议研究的目标是发展黑腹果蝇作为研究胎儿酒精综合征的动物模型。以前的研究表明，遗传因素可以调节酒精致畸风险的程度，但影响发育中乙醇毒性的特定基因的识别一直难以确定。这项拟议的研究将表征果蝇发育性酒精暴露后发生的发育、行为和神经解剖学变化，并确定改变发育性酒精毒性的新基因产品。初步数据显示，与对照动物相比，用5%乙醇食物饲养的苍蝇的存活率只有一半，而且发育时间明显延迟。此外，成年后，酒精饲养的果蝇对蒸发乙醇的运动刺激作用更加敏感，这表明酒精饲养会导致永久性的行为变化。为了明确乙醇致死的阶段和乙醇毒性的临界时间窗口，在不同发育阶段分别用0%和5%乙醇食物饲养动物。通常与胎儿酒精综合症相关的行为缺陷，如学习和记忆障碍，运动障碍，昼夜节律放松，以及饮食和睡眠障碍，将在酒精饲养的成年果蝇和未接触酒精的对照成年果蝇中进行评估。胎儿酒精综合征的行为障碍被认为是由酒精对发育中的中枢神经系统造成的损伤。因此，在胚胎和成年中枢神经系统中，将分别使用免疫细胞化学和GAL4/UAS双表达系统来检测发育过程中酒精暴露后的神经解剖损伤和/或改变。最后，将使用候选基因方法和对单基因插入突变的无偏见、正向遗传筛选来鉴定可改变乙醇致畸作用的基因产品。对调节乙醇致畸的基因的功能分析将通过分子、行为和遗传方法的组合进行。 与公共卫生相关：世界上胎儿酒精综合症的流行率为每1000名新生儿中有一至三名，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，有可能促进对酒精在发育过程中的作用的更好理解，并为制定预防(或减轻)产前酒精暴露的损害的策略指明方向。