Generating Mouse Mutants with Diabetic Nephropathy

产生患有糖尿病肾病的小鼠突变体

• 批准号: 6442192
• 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/6442192
• 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）： 在 人类苦难和公共卫生支出。大约有六％的 美国人口患有糖尿病，其中10-20％发展DN， 最终发展为终结阶段肾脏疾病（ESRD）。因素 为DN做出贡献仍然晦涩。虽然高血糖是必要的触发因素 单独的，这不足以引起DN。兄弟姐妹研究表明遗传很强 组成部分，但是定义了有助于人DN的特定遗传基因座 糖尿病的异质原因和 人类遗传背景的多样性。相反，广泛的可用性 基因同质小鼠菌株，再加上转基因的进展 技术，使小鼠独特地对分子进行解剖 疾病机制。与人一样，大多数小鼠不会患糖尿病 肾病和赋予DN敏感性的一系列基因 少数群体，尚未被描述。该提议是生成强大的 DN的鼠模型与人类疾病紧密相似；那是 遗传定义；并且可以轻松地在小鼠菌株之间传递。到 实现这些目标，我们建议确定转换的特定基因 “抗肾病抗性” C57BL/6应变为DN的菌株。我们会接受的 两种方法。第一个将使用“候选基因”方法。在人 易感DN的患者表现出比 那些对肾病的抗性。这些条件的处理减慢了 肾病的进展。血管紧张素原（ATG）eNOS和 易感患者已经描述了APOE等位基因。第一个特定 AIM将检查叠加高血压的人ATG的效果 在两个不同模型上 糖尿病，胰岛素缺乏HN6转基因小鼠和胰岛素耐药DB/DB 老鼠。第二种方法将尝试识别新型的主导修饰符 倾向于DN。糖尿病HNF6或DB/DB C57BL/6小鼠将被诱变 用乙基硝酸乙烯（ENU）和G 1后代筛选为DN（肾脏） 功能不全和/或蛋白尿）。这些研究不仅应该产生 定义明确的DN鼠标模型，但也提供了重要的新信息 关于有助于DN发展的基因。