Generating Mouse Mutants with Diabetic Nephropathy

描述(由申请人提供)： 糖尿病肾病是一种巨大的疾病，在以下两个方面 关于人类痛苦和公共卫生支出的数据。大约6%的人 美国人患有糖尿病，其中10%-20%患有糖尿病肾病， 最终发展为终末期肾病(ESRD)。影响因素 对域名的贡献仍不明朗。虽然高血糖是必要的触发因素， 仅有这一点还不足以导致糖尿病肾病。兄弟姐妹研究表明有很强的遗传 然而，定义了导致人类糖尿病肾病的特定遗传基因座 已经被糖尿病的不同原因以及 人类遗传背景的多样性。与之形成对比的是， 基因同源的小鼠品系与转基因研究进展 技术，使小鼠独特地服从于分子的解剖 疾病的机制。和人类一样，大多数小鼠不会患上糖尿病 肾病，以及导致糖尿病肾病易感性的一系列基因 少数人，还没有被描述出来。这项提议是为了产生一个健壮的 与人类疾病密切相关的糖尿病肾病小鼠模型；即 基因定义的；并且可以很容易地在小鼠品系之间转移。至 为了实现这些目标，我们建议确定特定的基因来转换 对肾病耐药的C57BL/6菌株对发生糖尿病肾病的菌株。我们会带上 有两种方法。第一个将使用“候选基因”方法。在人类身上， 易患糖尿病肾病患者的高血压和血脂异常比 对肾病有抵抗力的人。这些疾病的治疗会减缓 肾病的进展。血管紧张素原内皮型一氧化氮合酶基因的多态性 载脂蛋白E等位基因已在易感患者中被描述。第一个具体 目的研究叠加高血压人血管紧张素转换酶的效果。 两种不同模型的转基因、eNOS-/-或高脂血症ApoE-/-等位基因 糖尿病、胰岛素缺乏HN6转基因小鼠和胰岛素抵抗db/db 老鼠。第二种方法将试图确定新的主导修饰语 容易患上糖尿病肾病。糖尿病HNF6或db/db C57BL/6小鼠将被诱变 用乙基亚硝脲(ENU)和G1子代筛查DN(肾脏 功能不全和/或蛋白尿)。这些研究不仅应该产生一个 明确的糖尿病肾病小鼠模型，也提供了重要的新信息 关于促进糖尿病肾病发展的基因。

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.