Obesity and diabetes genetics and therapeutics in Caenorhabditis elegans.

秀丽隐杆线虫的肥胖和糖尿病遗传学和治疗。

• 批准号: 7669330
• 负责人: ALEXANDER A SOUKAS
• 金额: $ 4.33万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-24 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7669330
• 关键词: Affect; Aging; Biogenesis; Biological Assay; Body fat; Caenorhabditis elegans; Cessation of life; Cost of Illness; Defect; Development; Diabetes Mellitus; Disease; Energy Metabolism; Fatty acid glycerol esters; Fellowship; Future; Genes; Genetic; Genetic Epistasis; Genomics; Goals; Homeostasis; Homologous Gene; Human; Link; Lipids; Measurement; Messenger RNA; Metabolic; Metabolic Pathway; Microarray Analysis; Mitochondria; Molecular; Mutate; Nature; Neurosecretory Systems; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oligonucleotide Microarrays; Organism; Overweight; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Phenotype; Preclinical Drug Evaluation; RNA Interference; Regulation; Reporter; Research; Resistance; Role; Societies; Stress; System; Therapeutic; Tissues; Transgenic Organisms; Work; cell type; cost; diabetes mellitus genetics; feeding; fighting; food consumption; high throughput technology; interest; lipid metabolism; metabolomics; mitochondrial dysfunction; mutant; new technology; novel; premature; public health relevance; reproductive; small molecule; small molecule libraries; tandem mass spectrometry; years of life lost

DESCRIPTION (provided by applicant): This postdoctoral fellowship proposal outlines plans to use the organism Caenorhabditis elegans to identify genes involved in the pathogenesis of obesity and diabetes. Obesity and type 2 diabetes are extremely prevalent, highly associated diseases that cost the US more than $132 billion in 2002, and produce an even greater cost on society in terms of life-years lost. Specific aims are to use genomics (RNA interference) and forward genetics together with newly-available, high-throughput technology to perform saturating screens for novel genes which, when inactivated, cause defects in neuroendocrine regulation of body fat content or mitochondrial biogenesis. Genes emerging from the screens with close human homologues will be the subject of further study, since both dysregulated fat metabolism and mitochondrial dysfunction have been clearly implicated in the pathogenesis of type II diabetes. As many known genes important in human diabetes also cause aging, stress resistance or reproductive defects when mutated in C. elegans, assays for these pleiotropies will be conducted for each novel gene identified to affect fat or mitochondria. Mutants receiving priority scores in these assays will have energy homeostasis defects characterized in detail by quantitative assays for lipid content, food consumption, and energy expenditure. Genetic epistasis will identify which genes operate within known pathways or novel pathways regulating energy homeostasis. The tissue of expression and cell type of action will be established for interesting genes by transgenic reporter and tissue-specific rescue constructs. For the most promising fat and mitochondrial mutants, metabolomic profiling using tandem mass spectrometry and microarray mRNA profiling analysis will be conducted to further explore the molecular nature of metabolic defects. Finally, in order to identify possible obesity or diabetes therapeutics, a small-molecule library will be screened for compounds that reverse mutant phenotypes, i.e. obesity or mitochondrial defects. The ultimate goals of this work are to identify and characterize genes central to the pathogenesis of obesity and diabetes, to identify possible therapeutic molecules, and to create a platform to expand these efforts in the future. PUBLIC HEALTH RELEVANCE: Obesity and type 2 diabetes are tightly linked diseases well recognized to be among the leading causes of premature illness and death. Over one billion people are overweight and more than 200 million have diabetes worldwide. The proposed research fellowship aims to identify novel genes involved in the development of obesity and diabetes and possible drugs to fight these devastating diseases, using new technology and a genetic system in which the role of every single gene can be studied systematically.

描述（由申请人提供）：这个博士后奖学金提案概述了计划使用有机体秀丽隐杆线虫来识别参与肥胖和糖尿病发病机制的基因。肥胖和2型糖尿病是非常普遍的，高度相关的疾病，在2002年花费了美国超过1320亿美元，并且在生命年损失方面对社会产生更大的成本。具体目标是利用基因组学（RNA干扰）和正向遗传学以及新的可用的高通量技术，对新基因进行饱和筛选，这些基因在失活时会导致体脂含量或线粒体生物发生的神经内分泌调节缺陷。从筛选中出现的与人类同源的基因将成为进一步研究的主题，因为脂肪代谢失调和线粒体功能障碍都明确涉及II型糖尿病的发病机制。由于许多已知的基因在人类糖尿病中起重要作用，当C.在线虫中，将对每一个被鉴定为影响脂肪或线粒体的新基因进行这些多效性的测定。在这些测定中获得优先评分的突变体将具有能量稳态缺陷，其通过脂质含量、食物消耗和能量消耗的定量测定来详细表征。遗传上位性将确定哪些基因在已知的途径或新的途径中调节能量稳态。将通过转基因报告基因和组织特异性拯救构建体为感兴趣的基因建立表达的组织和作用的细胞类型。对于最有希望的脂肪和线粒体突变体，将使用串联质谱和微阵列mRNA谱分析进行代谢组学分析，以进一步探索代谢缺陷的分子性质。最后，为了鉴定可能的肥胖症或糖尿病治疗剂，将筛选小分子文库以获得逆转突变表型（即肥胖症或线粒体缺陷）的化合物。这项工作的最终目标是确定和表征肥胖和糖尿病发病机制的核心基因，确定可能的治疗分子，并创建一个平台，以扩大这些努力在未来。 公共卫生相关性：肥胖和2型糖尿病是密切相关的疾病，被公认为是过早患病和死亡的主要原因之一。全世界有超过10亿人超重，2亿多人患有糖尿病。拟议的研究奖学金旨在确定参与肥胖和糖尿病发展的新基因以及对抗这些毁灭性疾病的可能药物，使用新技术和遗传系统，其中每个基因的作用都可以系统地研究。