Genetic and genomic investigations of fat storage and metabolism in C. elegans

线虫脂肪储存和代谢的遗传和基因组研究

• 批准号: 7038927
• 负责人: Jennifer L Watts
• 金额: $ 31.86万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7038927
• 关键词: Caenorhabditis elegans; RNA interference; binding proteins; coenzyme A; enzyme activity; enzyme mechanism; fluorescent dye /probe; functional /structural genomics; gene expression profiling; gene mutation; genetic regulation; genetic regulatory element; genetic screening; genetic transcription; isozymes; lipid metabolism; metabolomics; obesity; oxygenases; stearates

DESCRIPTION (provided by applicant): Obesity afflicts millions of Americans and other people worldwide. The health problems associated with obesity are rising at epidemic rates, challenging world health care system to provide adequate care. The long-term goal of our research is to dissect the pathways of fat regulation to better understand the mechanisms by which interactions among specific genes act to either promote or facilitate resistance to obesity. Our genome-wide RNAi screen has identified 400 genes that, when inactivated, affect fat storage in C. elegans. We have also identified several C. elegans genes that influence obesity-related phenotypes. Mutant strains with reduced stearoyl-CoA desaturase (SCO) activity have reduced fat stores and the reduced ability to withstand periods of starvation when compared to wild type. Stearoyl-CoA desaturase is a key lipogenic enzyme that catalyzes the biosynthesis of monounsaturated fatty acids from saturated fatty acids. We intend to further characterize the SCO mutants, to determine which metabolic pathways are affected by the loss or reduction of this activity, and to further characterize regulators of SCO activity, including the nuclear hormone receptor nhr-80 and SREBP. In order to identify the metabolic and regulatory pathways that are affected by SCO, we will (1) use genome-wide RNAi screens to identify suppressors of the low fat phenotype of SCO-deficient strain, (2) examine the expression of a panel of metabolic genes in SCO deficient strains, as well as in mutants of regulators of SCO, and (3) use genome-wide approaches to identify genes necessary for the correct processing of C. elegans SREBP and to identify genes regulated by this central regulator of lipid homeostasis. C. elegans is amenable to large scale genetic and functional genomic screens that are not feasible in other systems. Using our collection of mutants and the powerful genetic and genomic resources available in C. elegans, we are now poised to provide a new level of understanding of the specific pathways affected by the stearoyl-CoA desaturases and their transcriptional activators in fat storage and metabolism

描述（由申请人提供）： 肥胖症困扰着数百万的美国人和其他全球。与肥胖相关的健康问题正在以流行病的速度增加，挑战世界医疗保健系统以提供足够的护理。我们研究的长期目标是剖析调节脂肪的途径，以更好地了解特定基因之间相互作用以促进或促进对肥胖的抗性的机制。我们全基因组的RNAi筛查已经确定了400个基因，这些基因在灭活后会影响秀丽隐杆线虫中的脂肪储存。我们还确定了几种影响与肥胖相关表型的秀丽隐杆线虫基因。与野生型相比，具有降低的硬糖酸氧化氢蛋白酶（SCO）活性降低的突变菌株具有降低的脂肪储存和承受饥饿周期的能力。 stearoyl-COA去饱和酶是一种关键的脂肪生成酶，可催化来自饱和脂肪酸的单不饱和脂肪酸的生物合成。我们打算进一步表征SCO突变体，以确定哪些代谢途径受此活性的丧失或减少影响，并进一步表征SCO活性的调节剂，包括核激素受体NHR-80和SREBP。为了确定SCO影响的代谢和调节途径，我们将使用（1）使用全基因组范围的RNAi筛选来识别SCO缺乏菌株低脂表型的抑制器，（（2）检查在SCO缺乏菌株中的代谢基因的表达，以及在SCO缺乏菌株中的良好方法，以及在SCO的突变中的命令，以及3）。秀丽隐杆线虫SREBP并鉴定由这种脂质稳态调节子调节的基因。秀丽隐杆线虫适合大规模的遗传和功能性基因组筛选，这些筛选在其他系统中不可行。使用我们的突变体的集合以及秀丽隐杆线虫中提供的强大遗传和基因组资源，我们现在准备提供对受stearoyl-COA去饱和酶影响的特定途径的新水平，及其在脂肪存储中的转录激活剂