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

肥胖困扰着数百万美国人和世界各地的其他人。与之相关的健康问题 肥胖症正在以流行病的速度上升，挑战着世界卫生保健系统提供足够的护理。的 我们研究的长期目标是剖析脂肪调节的途径，以更好地了解 特定基因之间的相互作用促进或促进对 肥胖我们的全基因组RNAi筛选已经确定了400个基因，这些基因在失活时会影响脂肪储存， C.优雅我们还发现了几个C。影响肥胖相关表型的基因。 具有降低的硬脂酰-CoA去饱和酶（SCO）活性的突变菌株具有降低的脂肪储存和降低的脂肪代谢。 与野生型相比，耐饥饿的能力。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 该活动的损失或减少，并进一步描述上海合作组织活动的监管机构，包括 核激素受体nhr-80和SREBP。为了确定代谢和调节途径 我们将（1）使用全基因组RNAi筛选来识别低脂肪的抑制因子， SCO缺陷型菌株的表型，（2）检测SCO中一组代谢基因的表达 缺陷菌株，以及在突变体的监管机构的SCO，和（3）使用全基因组的方法，以确定 正确加工C.线虫SREBP并鉴定受其调控的基因， 脂质体内平衡的中枢调节器。C.秀丽隐杆线虫适合大规模遗传和功能基因组学研究， 这在其他系统中是不可行的。利用我们收集的变种人和强大的基因， C.现有的基因组资源优雅，我们现在准备提供一个新的水平的理解， 脂肪储存中硬脂酰辅酶A去饱和酶及其转录激活因子影响的特定途径 和新陈代谢。

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.