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尤其有害，这对成年人的行为有长期影响。发育性乙醇暴露的毒性可归因于多种机制，包括乙醇代谢和相关的氧化应激、神经元细胞损失、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，但没有基因改变对FAS的易感性已被最终确定。我们的研究目的是利用遗传可适应的模式生物黑腹果蝇来识别和研究发育乙醇的分子靶点。黑腹果蝇（Drosophila melanogaster）是一种常见的果蝇，在生物学研究，特别是遗传学和发育研究中得到了广泛的应用。果蝇特别适合于复杂的遗传分析，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，一个多世纪的研究已经导致了基因组，分子和遗传工具的广泛收集，使果蝇在阐明基因功能方面非常强大。我们在果蝇中建立了FAS的遗传模型。我们已经证明，发育性乙醇暴露会导致生存能力降低和生长迟缓。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的影响，以及对表皮生长因子受体（EgfR）途径的影响。我们的研究将进一步阐明胰岛素信号在FAS发展中的作用，以及FAS的治疗方法

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.