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.

该提议的目的是建立新的遗传基础 小鼠模型可能更准确地类似于 人类的非胰岛素依赖性糖尿病（NIDDM）。 鼠标 NIDDM的模型应理想地将两种遗传易感性结合在一起 具有内在缺陷的肥胖/胰岛素抵抗的发展 胰腺β细胞功能。 非/lt菌株以及 NZO/H1菌株，表现出多基因肥胖。 两种菌株也表现出 胰腺β细胞对葡萄糖的固有缺陷 挑战。 非/lt小鼠只会降低葡萄糖耐受性， 而高血糖却在一些NZO/H1雄性中发展。 NZO的杂交 非雄性的女性会产生F1后代，这都逐渐发展 肥胖，但只有F1雄性会出现成熟 - 糖性高血糖。 与众不同 其他鼠肥胖引起的糖尿病模型，这些F1雄性是 以低胰岛素血症而不是高胰岛素血症为特征。 目的 该提案是通过F2分离分析来识别 造成NIDDM易感基因的染色体区域。 第二个 目的是建立携带nzo/lt的非/lt小鼠的多符号库存 携带NZO衍生的敏感性基因的小鼠会偏差 非小鼠对明显的NIDDM的葡萄糖耐量受损。 这将允许 NIDDM基因的精细映射，并测试β细胞的假设 非父母菌株的缺陷特征 共同表达产生更严重的NIDDM综合征。 决赛 目的是阐明男性的遗传和内分泌基础 NIDDM综合征在这种新的小鼠模型中的性限制性质。 如果 确定了控制β细胞缺陷的基因，该新模型将 对于更有效的药理学的测试和设计很重要 恢复正常β细胞功能的药物。