Genetic and Molecular Mechanisms of Ethanol-Induced Developmental Defects

描述（由申请人提供）：哺乳动物产前暴露于乙醇会导致一系列发育问题，从生长缺陷到智力迟钝和行为异常。在人类中，这些症状统称为胎儿酒精综合征（FAS）。酒精暴露对发育中的神经系统特别有害，这对成年人的行为有长期的影响。发育期乙醇暴露的毒性归因于多种机制，包括乙醇代谢和相关的氧化应激、神经元细胞损失以及生长因子和/或其信号转导途径的抑制。最后，虽然人类流行病学数据，双胞胎研究和动物模型表明，遗传因素赋予胎儿酒精损伤的风险和保护，但最终确定没有改变FAS易感性的基因。我们的研究目标是确定和研究的分子目标的发展乙醇使用的基因改造模式生物果蝇。 黑腹果蝇（Drosophilamelanogaster）是一种常见的果蝇，在生物学研究中被广泛利用，特别是在遗传学和发育方面。果蝇特别适合复杂的遗传分析，包括基因组方法，反向和分子遗传学，以及传统的正向遗传筛选。此外，经过世纪的研究，已经产生了大量的基因组、分子和遗传工具，使果蝇在阐明基因功能方面具有巨大的力量。 我们已经开发了一个遗传模型的FAS在苍蝇。我们已经表明，发育乙醇暴露导致活力降低和生长延迟。此外，与哺乳动物一样，用乙醇饲养的果蝇成年后对乙醇中毒的行为反应也发生了改变。最后，我们发现发育和行为缺陷是由于乙醇对胰岛素信号传导的影响，以及对表皮生长因子受体（EgfR）通路的影响。我们的研究将进一步阐明胰岛素信号在FAS发生中的作用，以及 鉴定发育期乙醇暴露的其他遗传和细胞靶点，包括胰岛素信号传导的下游和独立。我们的具体目标是：1）确定EgfR途径在乙醇对生长、活力和行为的影响中的作用，2）研究胰岛素信号传导在乙醇饲养的果蝇中耐受性发展中的作用，以及3）通过微阵列分析鉴定乙醇的分子靶点。

DESCRIPTION (provided by applicant): Prenatal exposure to ethanol in mammals leads to a range of developmental problems, from growth deficiency to mental retardation and behavioral abnormalities. In humans, these symptoms are collectively described as fetal alcohol syndrome (FAS). Ethanol exposure is especially damaging to the developing nervous system and this has long-term consequences on adult behavior. The toxicity of developmental ethanol exposure has been attributed to numerous mechanisms, including ethanol metabolism and related oxidative stress, neuronal cell loss, and inhibition of growth factors and/or their signal transduction pathways. Finally, while human epidemiological data, twin studies, and animal models indicate that genetic factors confer risk for and protection from fetal alcohol injury, no genes altering susceptibility to FAS have been conclusively identified. The goal of our research is to identify and study the molecular targets of developmental ethanol using the genetically amenable model organism Drosophila melanogaster. Drosophila melanogaster, the common fruit fly, has been utilized extensively in biological research, particularly in genetics and development. Drosophila are particularly amenable to sophisticated genetic analyses, including genomic approaches, reverse and molecular genetics, and traditional forward genetic screens. Moreover, over a century of research has led to an extensive collection of genomic, molecular and genetic tools, making Drosophila tremendously powerful in the elucidation of gene function. We have developed a genetic model of FAS in flies. We have shown that developmental ethanol exposure causes reduced viability and growth delay. In addition, as in mammals, flies reared on ethanol have altered behavioral responses to ethanol intoxication as adults. Finally, we have found that the developmental and behavioral defects are due to ethanol's effects on insulin signaling, as well as effects on the epidermal growth factor receptor (EgfR) pathway. Our research will further elucidate the role of insulin signaling in the development of FAS, as well as identify additional genetic and cellular targets of developmental ethanol exposure, both downstream and independent of insulin signaling. Our specific aims are: 1) to determine the role of the EgfR pathway in ethanol's effects on growth, viability, and behavior, 2) to investigate the role of insulin signaling in the development of tolerance in ethanol-reared flies, and 3) to identiy ethanol's molecular targets through microarray analysis.