Generating Mouse Mutants with Diabetic Nephropathy

产生患有糖尿病肾病的小鼠突变体

• 批准号: 6654901
• 负责人: Matthew Douglas Breyer
• 金额: $ 73.53万
• 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/6654901
• 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（申请人提供）： 糖尿病肾病（DN）是一种严重危害人类健康的疾病。 人类痛苦和公共卫生支出。大约百分之六的 美国人口患有糖尿病，其中10-20%发展为DN， 最终进展为终末期肾病（ESRD）。的因素 导致DN的原因仍不清楚。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 组成部分，但定义特定的遗传基因座有助于DN的人 被糖尿病的异质性原因所混淆， 人类遗传背景的多样性。相比之下， 基因同质的小鼠品系，加上转基因技术的进展， 技术，使小鼠特别适合解剖的分子 疾病的机制。和人类一样，大多数老鼠不会患糖尿病。 肾病，以及一系列赋予DN易感性的基因， 少数民族，没有特征。该提案旨在产生一个强大的 DN的小鼠模型与人类疾病密切相似;也就是说 遗传上确定的;并且可以容易地在小鼠品系之间转移。到 为了实现这些目标，我们建议确定特定的基因， “肾病抗性”C57 BL/6菌株与发展DN的菌株相比。我们将采取 两种方法。第一个将使用“候选基因”方法。在人身上， 易患DN的患者表现出比糖尿病患者更严重的高血压和血脂异常， 对肾病有抵抗力的人。这些疾病的治疗减缓了 肾病进展。血管紧张素原（Atg）eNOS和 已在易感患者中描述了ApoE等位基因。第一特定 目的是检查叠加高血压人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、胰岛素缺乏型HN 6转基因小鼠和胰岛素抵抗db/db 小鼠第二种方法将试图确定新的显性修饰语 容易患糖尿病肾病将对糖尿病HNF 6或db/db C57 BL/6小鼠进行诱变 用乙基亚硝基脲（ENU）和G1后代筛选DN（肾 功能不全和/或蛋白尿）。这些研究不仅应该产生一个 一个定义明确的DN小鼠模型，也提供了重要的新信息 关于导致糖尿病肾病的基因。