Genetic and Molecular Mechanisms of Ethanol-Induced Developmental Defects

描述(申请人提供)：哺乳动物出生前接触酒精会导致一系列发育问题，从生长缺陷到智力发育迟缓和行为异常。在人类身上，这些症状统称为胎儿酒精综合症(FAS)。酒精暴露对发育中的神经系统尤其有害，这会对成年人的行为产生长期影响。发育期酒精暴露的毒性被归因于多种机制，包括乙醇代谢和相关的氧化应激，神经细胞丢失，以及对生长因子和/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，但尚未确定任何改变Fas易感性的基因。我们的研究目标是利用遗传顺从的模式生物黑腹果蝇来鉴定和研究发育乙醇的分子靶标。黑腹果蝇是一种常见的果蝇，在生物学研究中有着广泛的应用，特别是在遗传和发育方面。果蝇特别容易接受复杂的遗传分析，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，一个多世纪的研究导致了广泛的基因组、分子和遗传工具的收集，使果蝇在阐明基因功能方面发挥了巨大的作用。我们已经开发出一种果蝇Fas的遗传模型。我们已经证明，发育中的乙醇暴露会导致生存能力下降和生长延迟。此外，与哺乳动物一样，以乙醇饲养的苍蝇在成年后改变了对乙醇中毒的行为反应。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发生中的作用，以及 确定发育中酒精暴露的其他遗传和细胞靶点，包括下游的和独立于胰岛素信号的。我们的具体目标是：1)确定EGFR通路在乙醇对生长、生存和行为影响中的作用；2)研究胰岛素信号在乙醇饲养的果蝇耐受发展中的作用；3)通过基因芯片分析确定乙醇的分子靶点。

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.