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）： 肥胖困扰着数百万美国人和世界各地的其他人。与肥胖相关的健康问题正在以流行病的速度上升，挑战世界卫生保健系统提供足够的护理。我们研究的长期目标是剖析脂肪调节的途径，以更好地理解特定基因之间的相互作用促进或促进对肥胖的抵抗的机制。我们的全基因组RNAi筛选已经确定了400个基因，这些基因在失活时会影响C.优美的我们还发现了几个C。影响肥胖相关表型的基因。与野生型相比，硬脂酰辅酶A去饱和酶（SCO）活性降低的突变株脂肪储存减少，耐受饥饿期的能力降低。硬脂酰辅酶A去饱和酶是催化饱和脂肪酸生物合成单不饱和脂肪酸的关键脂肪生成酶。我们打算进一步表征SCO突变体，以确定哪些代谢途径受到该活性丧失或减少的影响，并进一步表征SCO活性的调节因子，包括核激素受体nhr-80和SREBP。为了鉴定受SCO影响的代谢和调节途径，我们将（1）使用全基因组RNAi筛选来鉴定SCO缺陷型菌株的低脂表型的抑制因子，（2）检查一组代谢基因在SCO缺陷型菌株中的表达，以及在SCO调节因子的突变体中，和（3）使用全基因组方法来鉴定正确加工C.线虫SREBP，并确定由这个脂质稳态的中央调节器调控的基因。C.秀丽隐杆线虫适合于在其它系统中不可行的大规模遗传和功能基因组筛选。利用我们收集的突变体和强大的遗传和基因组资源在C。我们现在准备提供一个新的水平的理解的具体途径影响的硬脂酰辅酶A去饱和酶和他们的转录激活剂在脂肪储存和代谢