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型患者(胰岛素依赖型) 糖尿病和一些较少的非胰岛素依赖者 糖尿病导致了这种并发症。主要风险因素 促进糖尿病肾病发展的因素是代谢 控制(血糖控制差)、血流动力学因素(高血压、 肾血流、肾小球内毛细血管压力升高)和遗传 敏感度。非肥胖糖尿病(NOD)小鼠自发发育 继发于胰岛β细胞的I型(胰岛素依赖型)糖尿病 渗入的淋巴细胞和单核细胞造成的破坏(岛炎)。 糖尿病(男性和女性)出现后不久， NOD小鼠发生肾脏损害，包括弥漫性系膜损伤 与肾小球肥大、增厚相关的硬化症 肾小球基底膜，IV型胶原在肾小球中的积聚 肾小球系膜区与蛋白尿的发展。这些发现 与人类糖尿病患者的肾小球病变非常相似。 因此，点头老鼠提供了一个模型来研究 糖尿病肾小球硬化早期事件的发病机制。点头 鼠标代表了一个研究相互依赖或 胰岛素依赖型糖尿病与非胰岛素依赖型糖尿病 基因定义的动物模型中的肾小球硬化。我们的 初步观察表明，存在一个独立的 NOD小鼠糖尿病肾小球硬化基因的研究。独一无二的一点 我们项目的目的是利用野鼠的回交动物 小鼠品系，西班牙小鼠。西班牙代表斯普雷图斯博物馆 多个基因座的多态，不会发展为糖尿病和 肾小球硬化。 我们建议的研究旨在界定 这些小鼠肾小球损害的方式如下： A)建立第二代回交动物的平行系 西班牙斯普雷特斯鼠，糖尿病和岛炎的外显性 B)F1、第1和第2回交动物肾小球硬化的遗传 与西班牙斯普雷图斯博物馆点头 C)导致糖尿病的基因与 肾小球硬化程度 D)中国的微卫星和主要卫星标记的连锁分析 端粒和着丝粒与糖尿病肾病 利用聚合酶链式反应(PCR)和着丝粒分布(In 原位杂交)分析。 我们想强调的是，这笔赠款中的首席调查员 这项提案从未得到过来自 小灵通。

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.