NEW MOUSE MODELS OF DIABESITY

新的糖尿病小鼠模型

• 批准号: 6194024
• 负责人: EDWARD H LEITER
• 金额: $ 15.98万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-15 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6194024
• 关键词: blood glucose; chromosomes; diabetes mellitus genetics; disease /disorder model; gene expression; gene interaction; genetic strain; genome; glucose metabolism; glucose tolerance; homeostasis; insulin; laboratory mouse; lipid metabolism; liver metabolism; microarray technology; model design /development; molecular cloning; noninsulin dependent diabetes mellitus; obesity; pancreatic islets; phenotype; quantitative trait loci

DESCRIPTION: The objective of this proposal is to develop new mouse models that more accurately reflect the pathophysiology underlying the most commonly occurring forms of type II diabetes (NIDDM) in humans. Since type II diabetes is multigenic in origin, such models are needed no only to identify individual diabetes genes and their products, but also to discover how such genes interact with other genes and with the environment to trigger clinical disease. Deleterious polygenes from two unrelated parental strain genomes, when combined in hybrid combinations, produce a reproducible and sever obesity-induced diabetes ("diabesity"). The parental strains selected are New Zealand Obese (NZO/Lt) and NON/Lt. Each strain exhibits subphenotypes of obesity and impaired glucose tolerance considered to be essential components in NIDDM etiopathogenesis. NON/Lt male mice, selected for impaired glucose tolerance associated with impaired pancreatic beta cell glucose responsiveness, develop moderate maturity-onset obesity but fail to progress into overt diabetes. NZO males develop juvenile-onset obesity, but only a percentage exceeds a threshold necessary for diabetes to develop. Combining both genomes results in a diabesity syndrome wherein virtually all F1 males transit from impaired glucose tolerance into diabetes. Distinct quantitative trait loci (QTL) from both progenitor strains independently affecting plasma glucose and insulin levels were identified. A dominant NZO diabetes QTL on Chromosome 1 was identified that affected not only adiposity development, but also interacted epistatically with a locus on Chromosome 15 tightly linked to the Peroxisome Proliferator-Activated Receptor alpha (PPAR alpha) gene. A series of 9 QTL locus-directed recombinant congenic stocks (RCS) has been created by inbreeding at second backcross to the NON-parental strain. Males from one RCS line containing both the NZO diabetes QTL on Chromosome 1 and 15 develop diabetes, whereas another line carrying the Chromosome 1 diabesity QTL, but lacking the NZO susceptibility QTL on Chromosome 15 is diabetes resistant. Gene array technology is proposed to identify metabolic changes in liver and regional fat depots from these genetically similar, but diabesity-divergent sublines. This will permit identification of the key metabolic events associated with impaired lipid and glucose homeostasis in liver and fat, and permit elucidation of the metabolic basis underlying the diabetogenic Chromosome 1/15 interaction. Collectively, these studies will permit genetic and metabolic characterization of key events in the transition from simple obesity to diabesity in thee novel mouse models.

描述：本提案的目的是开发新的小鼠模型， 更准确地反映了最常见的 2型糖尿病（NIDDM）是人类的一种常见病。因为II型糖尿病 是多基因起源的，这样的模型不仅需要识别个体 糖尿病基因及其产物，但也要发现这些基因如何相互作用， 与其他基因和环境的相互作用引发临床疾病。 来自两个不相关亲本菌株基因组的有害多基因，当组合时 在杂交组合中，产生可重复的和严重的肥胖诱导的 糖尿病（“糖尿病”）。选择的亲本菌株是新西兰肥胖 (NZO/Lt）和NON/Lt。每种菌株均表现出肥胖和受损的亚表型 葡萄糖耐量被认为是NIDDM的重要组成部分 发病机理NON/Lt雄性小鼠，选择用于葡萄糖耐量受损 与胰腺β细胞葡萄糖反应受损相关， 中度成熟期肥胖，但未发展为显性糖尿病。恩佐 男性会出现青少年肥胖症，但只有一部分超过了临界值， 是糖尿病发展所必需的。结合两个基因组， 糖尿病综合征，其中几乎所有的F1雄性都从受损的葡萄糖 糖尿病的耐受性。来自两个不同的数量性状基因座（QTL） 独立影响血糖和胰岛素水平的祖细胞株 被确认了身份在1号染色体上鉴定了一个显性NZO糖尿病QTL 不仅影响肥胖的发展， 15号染色体上的一个位点与过氧化物酶体紧密相连 过氧化物酶体激活受体α基因。9个QTL 基因座定向重组同源原种（RCS）是通过近交产生的 在与非亲本品系的第二次回交时。一条RCS生产线的雄性 在1号和15号染色体上同时含有NZO糖尿病QTL的人发生糖尿病， 而另一个系携带1号染色体糖尿病QTL，但缺乏 15号染色体上的NZO易感性QTL是糖尿病抗性的。基因阵列 提出了一种技术来识别肝脏和局部脂肪的代谢变化， 从这些基因相似但糖尿病不同的亚系中提取。这 将允许识别与受损相关的关键代谢事件， 肝脏和脂肪中的脂质和葡萄糖稳态，并允许阐明 糖尿病发生的染色体1/15相互作用的代谢基础。 总的来说，这些研究将允许遗传和代谢特征 在这部小说中，从单纯性肥胖到糖尿病肥胖的转变过程中的关键事件 小鼠模型。