Role of drosophila Neuropeptide F in Ethanol Response

描述(申请人提供)：神经肽Y(NPY)信号系统在果蝇和哺乳动物之间在结构和功能上都是保守的。本实验室最近的研究表明，果蝇神经肽F(NPF)是果蝇基因组中单一的NPY同源物，在调节动机摄食、运动和酒精反应方面发挥着重要作用。在NPF基因缺陷果蝇和NPY基因敲除小鼠之间观察到了相似的表型：两种动物都表现出正常的基线摄食，但缺乏动力摄食；NPF基因缺陷果蝇幼虫表现出食物诱导的过度活动，而NPY基因敲除小鼠表现出更高的癫痫易感性；NPF基因缺陷果蝇和NPY基因敲除小鼠都表现出较低的酒精敏感性。此外，过量表达NPF的果蝇表现出对酒精镇静的敏感性增加，与NPY过度表达的小鼠的表型相似。这些观察结果有力地表明，果蝇是研究NPF/NPY信号系统作用的神经、细胞和分子机制的合适的遗传模型。 这项拟议的研究旨在进一步阐明心力衰竭的神经生物学基础。神经肽Y介导的酒精相关行为的调节。这一应用的具体目的包括：1)NPF系统参与乙醇反应调控的神经解剖部位的鉴定和功能分析；2)NPF/NPFR1介导的乙醇反应相关基因的EMS突变筛选；3)NPF/NPFR1介导的乙醇反应相关基因的功能获得筛选。这些研究的结果应该为理解为什么共同的神经信号系统是控制摄食和酒精相关行为的基础，信号通路的哪些组成部分是保守的，以及遗传因素如何在不同的生物体中促进酒精敏感性提供了新的见解。

DESCRIPTION (provided by applicant): The neuropeptide Y (NPY) signaling system is both structurally and functionally conserved between Drosophila and mammals. Recent studies from this laboratory have shown that Drosophila neuropeptide F (NPF), the single NPY homologue in the fly genome, plays important roles in modulating motivational feeding, locomotion and alcohol response. Parallel phenotypes have been observed between NPF-deficient flies and NPY-knockout mice: both animals displayed normal baseline feeding but deficits in motivational feeding; NPF-deficient fly larvae showed food-elicited hyperactive locomotion whereas NPY knockouts exhibited increased susceptibility to seizure; both NPF-deficient flies and NPY knockout mice displayed decreased ethanol sensitivity. Moreover, flies overexpressing NPF showed increased sensitivity to ethanol sedation, similar to the phenotypes of NPY-overexpressing mice. These observations strongly suggest that Drosophila is a suitable genetic model for the study of the neural, cellular and molecular mechanisms underlying the action the NPF/NPY signaling system. This proposed research aims to further elucidate the neurobiological basis of. NPY-mediated regulation of ethanol related behaviors. The specific aims of this application include: 1) Identification and functional analysis of the neuroanatomical sites of the NPF system involved in modulation of ethanol response; 2) EMS-mutagenesis screen of genes involved in NPF/NPFR1-mediated ethanol response; 3) gain-of-function screen for genes involved in NPF/NPFR1 -mediated ethanol response.. The results from these studies should provide novel insights into understanding why a common neural signaling system underlies the controls of feeding and alcohol related behaviors, what components of the signaling pathway are conserved, and how genetic factors contribute to ethanol sensitivity in diverse organisms