GENETIC SUSCEPTIBILITY TO DIABETIC NEPHROPATHY IN MICE

糖尿病肾病是糖尿病最可怕的并发症之一 糖尿病。 约30%至50%的I型（胰岛素依赖型）患者 糖尿病患者，非胰岛素依赖型糖尿病患者较少 糖尿病会出现这种并发症。 的主要危险因素 糖尿病肾病的发病机制有哪些 控制（血糖控制不良），血液动力学因素（高血压， 肾血流量升高，肾小球内毛细血管压）和遗传性 易感性 非肥胖糖尿病（NOD）小鼠自发发病 继发于胰岛β细胞的I型（胰岛素依赖型）糖尿病 被浸润的淋巴细胞和单核细胞破坏（胰岛炎）。 糖尿病出现后不久（男性和女性）， NOD小鼠出现肾脏病变，包括弥漫性系膜细胞 硬化与肾小球肥大，增厚 肾小球基底膜，IV型胶原的积累， 肾小球系膜区和蛋白尿的发展。 这些发现 与人类糖尿病患者中发现的肾小球病变非常相似。 因此，NOD小鼠提供了一种研究 糖尿病性肾小球硬化症早期事件的发病机制。 点头 鼠标代表了一个独特的机会，研究相互依存关系， 胰岛素依赖型糖尿病和 肾小球硬化症的基因定义的动物模型。 我们 初步观察表明，存在独立的 NOD小鼠中糖尿病的肾小球硬化基因。 唯一的一点 我们的项目是使用NOD小鼠与野生 小鼠品系，Mus spretus Spain。 Mus spretus西班牙代表 在许多基因座的多态性，并没有发展糖尿病， 肾小球硬化 我们提出的研究旨在确定遗传模式的 这些小鼠的肾小球病变以以下方式发生： a）建立NOD的第二次回交动物的平行系， 西班牙小家鼠与糖尿病和胰岛炎的发病 B）F1、第1代和第2代回交动物中肾小球硬化症的遗传 NOD with Mus spretus西班牙 c）致糖尿病基因和糖尿病基因之间的相互依赖性或缺乏相互依赖性。 肾小球硬化程度 d）微卫星和主要卫星标记在水稻中的连锁分析 端粒和着丝粒与糖尿病肾病 使用聚合酶链反应（PCR）和着丝粒分布（在 原位杂交）分析。 我们想强调的是， 该提案从未获得独立的研究资助， PHS。

Diabetic nephropathy is one of the most dreaded complications of diabetes mellitus. About 30% to 50% of patients with type I (insulin-dependent) diabetes mellitus and somewhat fewer of those with non-insulin-dependent diabetes mellitus develop this complication. The major risk factors contributing to the development of diabetic nephropathy are metabolic control (poor glycemic control), hemodynamic factors (hypertension, elevated renal flow, intraglomerular capillary pressure) and genetic susceptibility. The nonobese diabetic (NOD) mouse spontaneously develops type I (insulin-dependent) diabetes secondary to islet beta cell destruction by infiltrating lymphocytic and monocytic cells (insulitis). Shortly after the appearance of diabetes (both in males and females), the NOD mouse develops renal lesions which consist of diffuse mesangial sclerosis associated with glomerular hypertrophy, thickening of glomerular basement membrane, accumulation of type IV collagen in mesangial areas and the development of albuminuria. These findings closely mimic the glomerular lesions found in human diabetic patients. The NOD mouse, therefore, provides a model to investigate the pathogenesis of the early events of diabetic glomerulosclerosis. The NOD mouse represents a unique opportunity to study the interdependency or lack thereof between insulin-dependent diabetes mellitus and glomerulosclerosis in a genetically defined animal model. Our preliminary observation suggests the existence of an independent glomerulosclerosis gene of diabetes in the NOD mouse. The unique point of our project is the use of backcross animals of NOD mice with a wild mouse strain, Mus spretus Spain. Mus spretus Spain represent polymorphisms at many loci and do not develop diabetes and glomerulosclerosis. Our proposed studies aim to define the mode of inheritance of the glomerular lesions in these mice in the following ways: a) Establishment of parallel lines of 2nd backcross animals of NOD with Mus spretus Spain, and the penetrance of diabetes and insulitis b) Inheritance of glomerulosclerosis in F1, 1st and 2nd backcross animals of NOD with Mus spretus Spain c) Interdependency or lack thereof between the diabetogenic genes and the degree of glomerulosclerosis d) Linkage analysis of microsatellite and major satellite markers in the telomere and centromere with the kidney disease of diabetes mellitus using polymerase chain reaction (PCR) and centromere distribution (in situ hybridization) analyses. We would like to emphasize that the principal investigator in this grant proposal has never received independent research grant support from the PHS.