GLOMERULAR PERMSELECTIVITY IN ALPORT SYNDROME

描述(改编自申请者摘要)：Alport综合征是一种 一种遗传性肾病，由IV型胶原基因突变引起 组织结构的组成部分，称为基底膜。这些 突变导致肾小球基底IV型胶原缺陷 膜(GBM)，这是一种在防止 血液蛋白渗入尿液。蛋白尿(蛋白渗漏 进入尿液)是Alport综合征的一个重要特征。这样做的目的是 建议是：(1)了解Alport综合征蛋白尿是如何发展的 (2)检测环孢素A是否能减少原尿，预防肾脏 阿尔波特综合征失败。难以辨别的肾病 从遗传、生化和病理角度看，阿尔波特综合征 在狗身上是自发的。我们建议就这些问题进行三组研究 狗。(1)取病犬及正常犬肾小球 通过一系列的肾脏活检，我们将比较 受影响的肾小球和正常的肾小球到蛋白质。我们的假设是肾小球 Alport综合征早期对蛋白质的通透性是正常的，但 随着某些胶原蛋白在基底膜异常堆积而增加。(2)我们会 分离病变肾小球和正常肾小球的基底膜，检测肾小球基底膜是否异常 Alport基底膜成分对肾小球功能的影响 上皮细胞(GEC)附着于其上。GEC还发挥了预防作用 蛋白质渗入尿液。我们的假设是GEC不会依附于 正常连接到Alport GBM，并且该异常连接与 蛋白尿，并导致这些基因中某些基因活性的变化 细胞(3)目前没有治疗Alport肾病的方法，除了 肾移植。最近的一份报告描述了对蛋白尿的抑制 长期治疗对Alport患者肾功能的影响及稳定作用 用环孢素A。这项研究是非对照的，只包括8名患者。 此外，环孢素本身也会造成肾脏损害。出于这些原因 我们建议在狗身上进行环孢素治疗的对照试验 阿尔波特综合征。这项试验将比较尿蛋白水平、肾脏 治疗和未治疗犬的肾功能和肾脏结构变化。

DESCRIPTION (Adapted from the Applicant's Abstract): Alport syndrome is a genetic kidney disease that results from mutations in type IV collagen, an integral component of tissue structures known as basement membranes. These mutations result in defects in type IV collagen in the glomerular basement membrane (GBM), a structure that plays a critical role in preventing the leakage of blood proteins into the urine. Proteinuria (the leakage of proteins into the urine) is an important feature of Alport syndrome. The goals of this proposal are (1) to understand how proteinuria develops in Alport syndrome and (2) to test whether cyclosporine can reduce protienuria and prevent renal failure in Alport syndrome. Kidney disease that is indistinguishable genetically, biochemically and pathologically from Alport syndrome occurs spontaneously in dogs. We propose to perform three sets of studies on these dogs. (1) We will obtain glomeruli from affected dogs and their normal littermates by serial kidney biopsies, and we will compare the permeability of affected and normal glomeruli to protein. Our hypothesis is that glomerular permeability to protein is normal early in the course of Alport syndrome, but increases as certain collagens accumulate abnormally in the GBM. (2) We will isolate GBM from affected and normal glomeruli to test whether the abnormal composition of the Alport GBM interferes with the ability of glomerular epithelial cells (GEC) to attach to it. GEC also play a role in preventing protein leakage into the urine. Our hypothesis is that GEC do not attach normally to Alport GBM, and that abnormal attachment is associated with proteinuria, and results in changes in the activity of certain genes in these cells (3) There is currently no treatment for Alport kidney disease, other than renal transplantation. A recent report described suppression of proteinuria and stabilization of renal function in Alport patients by long-term treatment with cyclosporine. This study was uncontrolled and included only 8 patients. In addition, cyclosporine itself can cause kidney damage. For these reasons we propose to conduct a controlled trial of cyclosporine therapy in dogs with Alport syndrome. This trial will compare urinary protein levels, kidney function, and renal structural changes in treated and untreated dogs.