The Role of Insulin Signaling in Developmental Ethanol Toxicity

项目摘要： 发育期的乙醇暴露导致了多种有害的表型， 昆虫对人类的影响，包括生长缺陷，发育死亡率，代谢变化， 智力障碍和行为问题。在人类中，这些症状是共同的。 胎儿酒精谱系障碍（FASD）虽然流行病学证据表明 仅在美国，每年就有至少80，000例新的FASD病例， 目前还没有批准用于FASD的生物治疗。酒精暴露尤其是 对发育中的神经系统造成损害，这对成年人有长期的影响。 行为发育期乙醇暴露的毒性已被归因于许多 机制，包括乙醇代谢和相关的氧化应激，神经细胞损失， 抑制生长因子和/或其信号转导途径。特别是胰岛素和 胰岛素样生长因子（IGF）信号转导是乙醇发育的通用靶点 exposure.在哺乳动物中，由此产生的胰岛素抵抗导致对代谢产物的敏感性。 高脂饮食会加剧这种综合征。 我们研究的目标是利用基因上可接受的模式生物果蝇 黑腹动物，以确定发育乙醇暴露的分子靶点， 了解这些目标的破坏如何导致与以下相关的有害表型： 开发乙醇，并测试干预措施，可能有一天会导致治疗FASD 在人类身上。 黑腹果蝇（Drosophilamelanogaster）是一种常见的果蝇， 研究，特别是遗传学和发展。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， 和传统的遗传筛查此外，经过世纪的研究， 广泛收集基因组、分子、遗传和药理学工具， 果蝇在阐明基因功能方面非常强大。 我们已经建立和发展了一个果蝇FASD的遗传模型，并使用 该模型表明胰岛素信号传导被发育中的乙醇暴露破坏， 在发育过程中暴露于乙醇的果蝇具有与代谢相关的表型， 综合征我们也有第一个证据表明，饮食的变化可能会改善 乙醇对新陈代谢的发育影响。最后，我们发现， 暴露于酒精会导致进食不足，类似于暴露于酒精的哺乳动物中所观察到的情况。 乙醇，我们有证据表明这种表型也涉及胰岛素信号的改变。 我们的研究将进一步阐明胰岛素信号在FASD发展中的作用， 研究胰岛素信号传导、饮食和代谢易感性之间的相互作用， 综合征，以及测试DAE诱导的代谢综合征的可能治疗方法。在 此外，我们建议进一步阐明分子和神经元信号通路， 导致DAE触发的进食行为发生变化。我们的具体目标是：1）确定 饮食和胰岛素信号如何相互作用以介导发育中乙醇的毒性 暴露，以及2）研究胰岛素信号在异常摄食行为中的作用 这是由DAE产生的。

Project Summary: Developmental ethanol exposure causes a variety of deleterious phenotypes in taxa from insects to humans, including growth deficiency, developmental mortality, metabolic changes, intellectual disabilities, and behavior problems. In humans, these symptoms are collectively described as fetal alcohol spectrum disorder (FASD). Though epidemiological evidence suggests a minimum of 80,000 new cases of FASD every year in the United States alone, there is currently no approved biological treatment for FASD. 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. In particular, insulin and insulin-like growth factor (IGF) signaling is a universal target of developmental ethanol exposure. In mammals, the resulting insulin resistance leads to sensitivity to metabolic syndrome, which can be exacerbated by a high-fat diet. The goal of our research is to use the genetically amenable model organism Drosophila melanogaster to identify the molecular targets of developmental ethanol exposure, to understand how disruption of those targets leads to the deleterious phenotypes associated with developmental ethanol, and to test interventions that may one day lead to treatments for FASD in humans. Drosophila melanogaster, the common fruit fly, has been used 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, genetic, and pharmacological tools, making Drosophila tremendously powerful in the elucidation of gene function. We have established and developed a genetic model of FASD in flies, and have used this model to show that insulin signaling is disrupted by developmental ethanol exposure, and that flies exposed to ethanol during development have phenotypes consistent with metabolic syndrome. We also have the first evidence that dietary changes may ameliorate the developmental effects of ethanol on metabolism. Finally, we discovered that developmental exposure to alcohol causes feeding deficits similar to those seen in mammals exposed to ethanol, and we have evidence implicating altered insulin signaling in this phenotype as well. Our research will further elucidate the role of insulin signaling in the development of FASD, by investigating the interaction between insulin signaling, diet, and predisposition to metabolic syndrome, as well as testing possible treatments for DAE-induced metabolic syndrome. In addition, we propose to further elucidate the molecular and neuronal signaling pathways that lead to changes in feeding behavior triggered by DAE. Our specific aims are: 1) to determine how diet and insulin signaling interact to mediate the toxicity of developmental ethanol exposure, and 2) to investigate the role of insulin signaling in the abnormal feeding behaviors that result from DAE.