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: 7545454
• 负责人: Jennifer L Watts
• 金额: $ 27.94万
• 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 2010-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7545454
• 关键词: Adverse effects; Affect; American; Anabolism; Animal Model; Biology; Caenorhabditis elegans; Cardiovascular Diseases; Caring; Cell Nucleus; Collaborations; Collection; Complex; Diabetes Mellitus; Drug Design; Enzymes; Epidemic; Exhibits; Fatty acid glycerol esters; Genes; Genetic; Genetic Screening; Genomics; Goals; Health; Healthcare Systems; Homeostasis; Hypertension; Incidence; Investigation; Isoenzymes; Lead; Lipids; Malignant Neoplasms; Measures; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular; Monounsaturated Fatty Acids; Mutation; Nuclear Hormone Receptors; Obesity; Pathway interactions; Pattern; Phenotype; Process; Proteins; RNA Interference; Regulation; Regulatory Pathway; Reporter; Research; Resistance; Resources; Role; Saturated Fatty Acids; Starvation; Stearoyl-CoA Desaturase; System; Transcription Coactivator; Triglycerides; Weight Gain; Work; World Health; base; combat; drug discovery; fatty acid oxidation; functional genomics; genome-wide; mutant; novel; research study; tool

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.

肥胖症困扰着数百万的美国人和其他全世界的其他人。与健康问题有关 肥胖以流行病的增加，挑战世界卫生保健系统以提供足够的护理。这 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 特定基因之间相互作用起来促进或促进抵抗力的机制 肥胖。我们的全基因组RNAi屏幕已经确定了400个基因，当灭活时，会影响脂肪储存 秀丽隐杆线。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。 降低的耐羟基-COA去饱和酶（SCO）活性的突变菌株减少了脂肪储存，降低了 与野生型相比，能够承受饥饿时期的能力。 stearoyl-COA去饱和酶是关键 脂肪生成酶催化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到影响 该活动的丧失或减少，并进一步表征SCO活动的调节剂，包括 核激素受体NHR-80和SREBP。为了确定代谢和调节途径 受到SCO影响的，我们将（1）使用全基因组RNAi筛选来识别低脂的抑制剂 SCO缺陷菌株的表型，（2）检查SCO中代谢基因的表达 不足的菌株以及SCO调节剂的突变体，（3）使用全基因组方法来识别 正确加工秀丽隐杆线虫SREBP所需的基因，并确定由此调节的基因 脂质稳态的中央调节剂。秀丽隐杆线虫适合大规模遗传和功能基因组 在其他系统中不可行的屏幕。使用我们集合的突变体和强大的遗传和 秀丽隐杆线虫可用的基因组资源，我们现在准备提供对对 脂肪存储中受stearoyl-COA去饱和酶及其转录激活剂影响的特定途径 和新陈代谢。