Generating Mouse Mutants with Diabetic Nephropathy

产生患有糖尿病肾病的小鼠突变体

• 批准号: 6941309
• 负责人: Matthew Douglas Breyer
• 金额: $ 97.06万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6941309
• 关键词: angiotensinogen; apolipoprotein E; blood chemistry; cooperative study; diabetes mellitus; diabetes mellitus genetics; diabetic nephropathy; disease /disorder model; electron microscopy; gene expression; gene targeting; genetic susceptibility; genetically modified animals; histopathology; hyperglycemia; hyperlipidemia; hypertension; immunocytochemistry; insulin sensitivity /resistance; kidney function; laboratory mouse; microarray technology; model design /development; molecular pathology; nitric oxide synthase; protein structure function

DESCRIPTION (Provided by Applicant): Diabetic nephropathy (DN) is a disease of monumental proportions both in terms of human suffering and public health expenditures. Approximately six percent of the U.S. population has diabetes mellitus, 10-20% of which develop DN, ultimately progressing to end stage renal disease (ESRD). The factors contributing to DN remain obscure. While hyperglycemia is a necessary trigger, alone, it is insufficient to cause DN. Sibling studies suggest a strong genetic component, however defining the specific genetic loci contributing to DN in man has been confounded by the heterogeneous causes of diabetes, and by the diversity of human genetic background. In contrast, the wide availability of genetically homogenous mouse strains, coupled with advances in transgenic technology, make mice uniquely amenable to dissection of the molecular mechanisms of disease. As in man, most mice do not develop diabetic nephropathy, and the array of genes that confer susceptibility to DN to this minority, have not been characterized. This proposal is to generate a robust murine model of DN that closely parallels the human disease; that is genetically defined; and can be easily transferred between mouse strains. To achieve these goals we propose to identify specific genes that convert the "nephropathy resistant" C57BL/6 strain to one that develops DN. We will take two approaches. The first will use a "candidate gene" approach. In man, patients susceptible to DN exhibit worse hypertension and dyslipidemia than those resistant to nephropathy. Treatment of these conditions slows the progression of nephropathy. Polymorphisms in Angiotensinogen (Atg) eNOS and ApoE alleles have been described in susceptible patients. The first specific aim will examine the effect of superimposing the hypertensive human Atg transgenic, eNOS-/- or hyperlipidemic ApoE-/- alleles on two different models of diabetes, insulin deficient HN6 transgenic mice and insulin resistant db/db mice. The second approach will attempt to identify novel dominant modifiers that predispose to DN. Diabetic HNF6 or db/db C57BL/6 mice will be mutagenized with ethylnitrosourea (ENU) and G 1 offspring screened for DN (renal insufficiency and/or proteinuria). These studies should not only yield a well-defined mouse model of DN, but also provide important new information regarding genes that contribute to the development of DN.

描述（由申请人提供）： 糖尿病肾病 (DN) 是一种影响深远的疾病 人类苦难和公共卫生支出。大约百分之六 美国人口患有糖尿病，其中 10-20% 患有 DN， 最终进展为终末期肾病（ESRD）。因素 对 DN 的贡献仍不清楚。虽然高血糖是一个必要的触发因素， 单独使用不足以引起 DN。兄弟姐妹研究表明强大的遗传 然而，定义导致人类 DN 的特定遗传位点 糖尿病的异质性病因以及 人类遗传背景的多样性。相比之下，广泛的可用性 遗传同质的小鼠品系，加上转基因技术的进步 技术，使小鼠特别适合分子解剖 疾病机制。与人类一样，大多数小鼠不会患上糖尿病 肾病，以及赋予 DN 易感性​​的一系列基因 少数，尚未被表征。该提案旨在产生一个稳健的 DN 小鼠模型与人类疾病非常相似；那是 基因定义的；并且可以在小鼠品系之间轻松转移。到 为了实现这些目标，我们建议识别能够转化的特定基因 “肾病抗性”C57BL/6 菌株转变为发展为 DN 的菌株。我们将采取 两种方法。第一个将使用“候选基因”方法。在男人身上， 易患 DN 的患者表现出更严重的高血压和血脂异常 对肾病有抵抗力的人。治疗这些病症会减慢 肾病的进展。血管紧张素原 (Atg) eNOS 和 已在易感患者中描述了 ApoE 等位基因。第一个具体 目的将检验叠加高血压人体Atg的效果 两种不同模型上的转基因、eNOS-/- 或高脂血症 ApoE-/- 等位基因 糖尿病、胰岛素缺乏的 HN6 转基因小鼠和胰岛素抵抗 db/db 老鼠。第二种方法将尝试识别新的主导修饰符 易患 DN。糖尿病 HNF6 或 db/db C57BL/6 小鼠将被诱变 乙基亚硝基脲 (ENU) 和 G 1 后代筛查 DN（肾 不足和/或蛋白尿）。这些研究不仅应该产生 明确定义的 DN 小鼠模型，还提供重要的新信息 关于有助于 DN 发展的基因。