GLOMERULAR PERMSELECTIVITY IN ALPORT SYNDROME

描述（改编自申请人的摘要）：Alport综合征是一种 由IV型胶原蛋白突变引起的遗传性肾病， 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），一种在防止细胞凋亡中起关键作用的结构。 血液蛋白渗漏到尿液中。 蛋白尿（蛋白质的渗漏 进入尿液）是Alport综合征的一个重要特征。 这个的目标 建议是（1）了解蛋白尿如何在Alport综合征中发展， (2)检测环孢素是否能减少蛋白尿， Alport综合征 无法区分的肾脏疾病 从遗传、生化和病理学角度来看， 在狗身上自发的。 我们建议进行三组研究， 狗(1)我们将从受影响的狗和他们的正常肾小球 通过一系列肾脏活检，我们将比较 受影响和正常的肾小球蛋白质。 我们的假设是肾小球 在Alport综合征的早期，蛋白质渗透性是正常的，但 随着某些胶原蛋白在GBM中异常积累而增加。 (2)我们将 从受影响的和正常的肾小球分离GBM，以测试是否异常 Alport GBM的组成干扰肾小球的能力， 上皮细胞（GEC）附着于其上。GEC还在防止 蛋白质进入尿液我们的假设是GEC不附着在 正常Alport GBM，并且异常附件与 蛋白尿，并导致这些细胞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抑制蛋白尿 Alport患者长期治疗后肾功能稳定 环孢霉素 该研究未设对照，仅纳入8例患者。 此外，环孢素本身可引起肾脏损害。 由于这些原因 我们建议在患有以下疾病的狗中进行环孢霉素治疗的对照试验： Alport综合征 这项试验将比较尿蛋白水平，肾脏 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.