Genetic analysis of sphingolipid metabolism and obesity

描述（由申请人提供）： 拟议研究的长期目标将是深入了解鞘脂在肥胖病因学中的作用。这些研究将使用果蝇作为模式遗传生物，以检查当调节鞘脂代谢的基因被破坏时，肥胖特征发展的机制。提出了六个具体目标： (1)编码调节鞘脂代谢的关键酶的基因的表达谱将在成年果蝇中绘制。 (2)将创建系统性破坏鞘脂代谢并导致肥胖的遗传模型。 (3)将在鞘脂代谢突变体和转基因果蝇品系中生成鞘脂、甘油三酯和胆固醇的脂质谱。 (4)将对鞘脂代谢突变体和转基因生物的肥胖表型进行表征 (5)将检查通过SREPB加工的脂肪酸生物合成途径的调节。 (6)将进行遗传筛选，以确定参与鞘脂代谢突变体中肥胖症发展和肥胖症表型修饰剂的新基因。 预计拟议的研究将为理解鞘脂代谢与肥胖之间的关系奠定坚实而新颖的基础，并可能揭示管理这些途径的新调控机制。

DESCRIPTION (provided by applicant): The long-term objectives of the proposed research will be will be to gain insight into the involvement of sphingolipids in the etiology of obesity. These studies will use Drosophila as a model genetic organism to examine the mechanisms that underlie the development of obese characteristics when genes that regulate sphingolipid metabolism are disrupted. Six specific aims are proposed: (1) The expression profiles of genes encoding key enzymes that regulate sphingolipid metabolism will be mapped in adult flies. (2) Genetic models that systematically disrupt sphingolipid metabolism and cause obesity will be created. (3) Lipid profiles of sphingolipids, triglycerides and cholesterol will be generated in sphingolipid metabolic mutant and transgenic fly lines. (4) Obesity phenotypes of sphingolipid metabolic mutants and transgenic organisms will be characterized (5) Regulation of the fatty acid biosynthetic pathway via SREPB processing will be examined. (6) Genetic screens will be performed to identify novel genes involved in the development of obesity and modifiers of obesity phenotypes in sphingolipid metabolic mutants. It is anticipated that the proposed studies will form a firm and novel foundation for understanding the relationships between sphingolipid metabolism and obesity and may uncover novel regulatory mechanisms that govern these pathways.