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节，因此体重可以在很长一段时间内保持恒定，尽管食物摄入量和活动量不同。这种稳态表明存在强有力的调节机制，大多数生物学机制都有潜在的遗传基础。 20世纪60年代分离出的果蝇脂肪突变证明果蝇可以变得肥胖，因为该突变导致成年果蝇的总脂肪含量加倍。 果蝇作为实验生物的优势不仅在于它能够进行大规模、快速和廉价的遗传筛选，而且还在于多年的遗传分析，其基因组的完整序列使其相对容易识别和克隆具有有趣突变表型的基因。果蝇被成功用作模型的生物学问题清单令人印象深刻，包括确定调节昼夜节律的基因，行为方面，如学习和记忆，以及神经系统发育。这些基因中的许多为发现它们的哺乳动物同源物提供了线索。果蝇在肥胖研究中的应用为大规模基因筛选开辟了前景，以确定负责食欲控制、体重调节和脂肪储存的基因，并分析潜在的生物学机制。我们已经分离出一系列果蝇的肥胖突变体。该项目的具体目标将是描述其表型，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性肥胖缺陷。

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.