The Role of Insulin Signaling in Developmental Ethanol Toxicity

项目总结： 发育中的乙醇暴露会导致来自 昆虫对人类的影响，包括生长缺陷、发育死亡、代谢变化、 智力残疾和行为问题。在人类身上，这些症状统称为 被描述为胎儿酒精谱系障碍(FASD)。虽然流行病学证据 建议每年至少有8万例FASD新病例，仅在美国，那里 目前还没有批准用于FASD的生物治疗。酒精暴露尤其是 损害发育中的神经系统，这对成年人有长期的影响 行为。发育期酒精暴露的毒性被归因于许多 机制，包括乙醇代谢和相关的氧化应激，神经细胞丢失，以及 抑制生长因子和/或其信号转导途径。尤其是胰岛素和 胰岛素样生长因子(IGF)信号转导是发育酒精的普遍靶点 曝光。在哺乳动物中，由此产生的胰岛素抵抗会导致对代谢的敏感 综合症，高脂肪饮食会加剧这种症状。 我们的研究目标是利用遗传上可服从的模式生物果蝇 以确定发育性酒精暴露的分子靶点，以 了解这些靶点的破坏如何导致与以下相关的有害表型 发育性乙醇，并测试有朝一日可能导致FASD治疗的干预措施 在人类身上。 黑腹果蝇是一种常见的果蝇，在生物学上有着广泛的应用 研究，特别是在遗传学和发展方面。果蝇特别容易受到 复杂的遗传分析，包括基因组方法、反向和分子遗传学， 和传统的前向基因筛查。此外，一个多世纪的研究已经导致了一种 广泛收集基因组、分子、遗传和药理学工具，使 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果蝇FASD的遗传模型，并使用了 这一模型表明，发育中的乙醇暴露会扰乱胰岛素信号，并且 在发育过程中暴露在乙醇中的果蝇的表型与新陈代谢一致 综合症。我们也有第一个证据表明，改变饮食可能会改善 乙醇对新陈代谢的发育影响。最后，我们发现发展中的 暴露在酒精中会导致摄食不足，与暴露在酒精中的哺乳动物相似 乙醇，我们也有证据表明胰岛素信号在这种表型中发生了变化。 我们的研究将通过以下方式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、饮食和代谢易感性之间的相互作用 以及测试DAE诱导的代谢综合征的可能治疗方法。在……里面 此外，我们建议进一步阐明分子和神经元信号通路 导致DAE触发的喂食行为发生变化。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来调节发育性乙醇的毒性 2)研究胰岛素信号在异常摄食行为中的作用。 这是DAE的结果。

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.