NEW MOUSE MODELS OF DIABESITY

描述：这项提议的目标是开发新的老鼠模型， 更准确地反映出最常见的 人类II型糖尿病(NIDDM)的发生形式。从II型糖尿病开始 是多基因起源的，这样的模式不仅仅是为了识别个体 糖尿病基因及其产物，而且还发现这些基因是如何相互作用的 与其他基因和环境一起引发临床疾病。 来自两个不相关亲本菌株基因组的有害多基因组合 在杂交组合中，产生可重复和严重肥胖诱导的 糖尿病(“糖尿病”)。选定的亲本菌株为新西兰肥胖症 (NZO/LT)和NON/LIT.每个菌株都表现出肥胖和受损的亚型 糖耐量被认为是NIDDM的重要组成部分 病因病机。非/lt雄性小鼠，选择糖耐量受损 与胰岛β细胞葡萄糖反应性受损相关，发生 中度成熟发作性肥胖，但不会发展为显性糖尿病。恩佐 男性患青少年肥胖症，但只有一个百分比超过门槛 对糖尿病的发展是必要的。将这两个基因组组合在一起会产生一种 肥胖综合征，几乎所有F1男性都是从血糖受损过渡而来的 对糖尿病的耐受性。两个不同的数量性状座位(QTL) 独立影响血糖和胰岛素水平的祖细胞株 都被确认了。在1号染色体上定位了一个显性的Nzo糖尿病QTL 这不仅影响了肥胖症的发展，而且还在上位上相互作用 在15号染色体上有一个与过氧化物体紧密连锁的基因座 增殖因子激活受体α(PPARα)基因。一系列9个QTL 基因座导向的重组同源群体(RCS)是通过近交产生的 在与非亲本品系的第二次回交时。来自一个RCS系的雄性 在1号和15号染色体上同时含有NZO糖尿病QTL的人会患上糖尿病， 而另一株系携带1号染色体肥胖QTL，但缺乏 位于15号染色体上的NZO易感QTL是抗糖尿病的。基因阵列 这项技术被用来识别肝脏和局部脂肪的代谢变化。 来自这些遗传相似但肥胖差异不同的亚系的仓库。这 将允许识别与受损相关的关键代谢事件 肝脏和脂肪中的脂肪和葡萄糖的动态平衡，并允许澄清 糖尿病致1/15染色体相互作用的代谢基础。 总的来说，这些研究将使遗传和新陈代谢表征成为可能。 在你的小说中从单纯性肥胖向肥胖症过渡的关键事件 老鼠模型。

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.