NEW MODELS FOR IDENTIFYING NIDDM POLYGENES

鉴定 NIDDM 多基因的新模型

• 批准号: 6122951
• 负责人: EDWARD H LEITER
• 金额: $ 10.65万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2000-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6122951
• 关键词: NOD mouse; diabetes mellitus genetics; disease /disorder model; disease /disorder proneness /risk; genetic markers; genetic strain; genetically modified animals; glucose tolerance; laboratory mouse; linkage mapping; male; model design /development; noninsulin dependent diabetes mellitus; obesity; pancreatic islets; phenotype; sex linked trait

The aim of this proposal is to establish the genetic basis for a new mouse model that may more accurately resemble the etiopathogenesis of non-insulin dependent diabetes mellitus (NIDDM) in humans. A mouse model of NIDDM should ideally combine both a genetic predisposition to development of obesity/insulin resistance with an intrinsic defect in pancreatic beta cell function. Both the NON/Lt strain, as well as the NZO/H1 strain, exhibit polygenic obesity. Both strains also exhibit intrinsic defects in pancreatic beta cell responsiveness to glucose challenge. NON/Lt mice progress only to impaired glucose tolerance, whereas hyperglycemia develops in some NZO/H1 males. Outcrossing of NZO females to NON males produces F1 progeny which all progressively develop obesity, but only F1 males develop maturity-onset hyperglycemia. Unlike other murine obesity-induced diabetes models, these F1 males are characterized by hypoinsulinemia rather than hyperinsulinemia. The aims of this proposal are to identify by F2 segregation analysis the chromosomal regions contributing Niddm susceptibility genes. The second aim is to establish polycongenic stocks of NON/Lt mice carrying NZO/Lt mice carrying NZO-derived susceptibility genes that will deviate the impaired glucose tolerance of NON mice to overt NIDDM. This will allow fine mapping of the Niddm genes, and test the hypothesis that beta cell defects characteristic of both the NON and NZO parental strains codominantly express to produce a more severe NIDDM syndrome. The final aim is to elucidate the genetic and endocrinologic basis for the male sex-limited nature of the NIDDM syndrome in this new mouse model. If genes controlling beta cell defects are identified, this new model will be important for testing and design of more effective pharmacologic agents for restoration of normal beta cell functions.

该提案的目的是为新的基因奠定遗传基础。 可能更准确地模拟发病机制的小鼠模型 人类非胰岛素依赖型糖尿病（NIDDM）。 一只老鼠 NIDDM 模型理想地应将遗传倾向与 肥胖/胰岛素抵抗的发展具有内在缺陷 胰腺β细胞功能。 NON/Lt 菌株以及 NZO/H1 菌株，表现出多基因肥胖。 两种菌株还表现出 胰腺β细胞对葡萄糖反应的内在缺陷 挑战。 NON/Lt 小鼠仅进展为糖耐量受损， 而一些 NZO/H1 男性会出现高血糖。 NZO异交 雌性与非雄性产生 F1 后代，所有后代均逐渐发育 肥胖，但只有 F1 雄性才会出现成熟期高血糖。 不像 其他小鼠肥胖诱发的糖尿病模型，这些 F1 雄性是 其特征是低胰岛素血症而不是高胰岛素血症。 目标 该提案的目的是通过 F2 分离分析来确定 贡献 Niddm 易感基因的染色体区域。 第二个 目的是建立携带NZO/Lt的NON/Lt小鼠的多同源种群 携带NZO衍生易感基因的小鼠会偏离 NON 小鼠对明显 NIDDM 的糖耐量受损。 这将允许 Niddm 基因的精细定位，并检验 β 细胞的假设 NON 和 NZO 亲本菌株的缺陷特征 共显性表达可产生更严重的 NIDDM 综合征。 决赛 目的是阐明男性的遗传和内分泌基础 在这个新的小鼠模型中，NIDDM 综合征的性别限制性质。 如果 确定了控制 β 细胞缺陷的基因，这个新模型将 对于测试和设计更有效的药理学很重要 恢复正常β细胞功能的药物。