Drosophila Model for Genetics of Obesity

描述(由申请人提供)： 肥胖是一种复杂的疾病，由食物摄入和能量消耗之间的不平衡引起。这些过程通常受到精确的调控，因此，尽管食物摄入量和活动量不同，但体重可以在很长一段时间内保持不变。这种动态平衡表明存在强大的调节机制，而大多数生物机制都有潜在的遗传基础。 20世纪60年代S对果蝇脂肪突变的分离表明，果蝇可以变得肥胖，因为这种突变会使成年果蝇的总脂肪含量翻一番。 果蝇作为实验有机体的优势不仅在于其适应大规模、快速、廉价的基因筛选，还在于多年的遗传分析，随着其基因组全序列的完成而达到高潮，这使得识别和克隆具有有趣突变表型的基因变得相对容易。果蝇被成功用作模型的一系列生物学问题令人印象深刻，包括调节昼夜节律的基因的识别，学习和记忆等行为方面的识别，以及神经系统的发育。这些基因中的许多都为发现它们在哺乳动物中的同源物提供了线索。果蝇在肥胖研究中的应用开启了大规模基因筛查的前景，以确定负责食欲控制、体重调节和脂肪储存的基因，以及分析潜在的生物机制。我们已经分离出一系列肥胖的果蝇突变体。该项目的具体目标将是表征它们的表型，克隆基因，分析受影响的生化途径，并分离抑制基因以逆转遗传肥胖缺陷。

DESCRIPTION (provided by applicant): Obesity is a complex disorder caused by an imbalance between food intake and energy expenditure. These processes normally are precisely regulated, so that body weight can remain constant over a long time, in spite of variable food intake and activity. This homeostasis suggests the presence of strong regulatory mechanisms, and most biological mechanisms have an underlying genetic basis. The isolation of the Drosophila adipose mutation in the 1960's demonstrated that Drosophila can become obese, since that mutation causes a doubling in the overall fat content of adult flies. The strength of Drosophila as an experimental organism lies not only in its amenability to large scale, fast, and cheap genetic screening, but also in many years of genetic analysis, climaxing with the complete sequence of its genome, which makes it relatively easy to identify and clone genes with interesting mutant phenotypes. The list of biological problems for which Drosophila has been used successfully as a model is impressive, including the identification of genes that regulate the circadian rhythm, aspects of behavior such as learning and memory, and nervous system development. Many of these genes have provided clues to the discovery of their mammalian homologs. The use of Drosophila in obesity research opens the prospect of large-scale genetic screens to identify genes responsible for appetite control, body weight regulation, and fat storage, as well as analysis of the underlying biological mechanisms. We have isolated a series of obese mutants of Drosophila. The specific aims of the project will be to characterize their phenotypes, clone the genes, analyze the affected biochemical pathways, and isolate suppressor genes to reverse the genetic obesity defects.