RENAL FAILURE IN HEREDITARY NEPHRITIS--GENESIS & THERAPY

描述（直接摘自申请人摘要） Alport综合征是一种遗传性肾脏疾病， 耳聋，由IV型胶原蛋白的遗传异常引起， 组织结构的组成部分称为基底膜。 在 大多数患有Alport综合征的家庭，这种疾病是作为X连锁传播的。 占主导地位的条件，受影响的男性发展肾衰竭，在青春期 或年轻的成年人。 虽然最近人们对遗传学有了很多了解， Alport综合征，疾病进展的机制 对肾衰竭的影响还不清楚。 目前没有 治疗Alport肾病，肾移植除外。 肾脏疾病是无法区分的遗传，生化和 病理学上Alport综合征在一些狗中自发发生 家庭 这些狗提供了测试潜在治疗的机会， Alport综合征的干预措施，并阐明其发病机制， 肾衰竭的症状 本申请中提出的研究是 基于以下假设：（1）Alport综合征的肾功能衰竭 由肾脏中特定胶原类型的积累引起， 由原发性遗传缺陷引发并由TGF-b1驱动;和（2） 抑制血管紧张素转换酶可以减缓进展速度 肾衰竭，通过抑制TGF-β 1活性， 肾脏中胶原蛋白的积聚。 假设1将由以下人员进行检验： 在狗家族的受影响雄性成员中进行连续肾活检 患有遗传性肾炎（所谓的“纳瓦索塔狗”）。 的程度 这些活检组织中的胶原蛋白积聚和TGF-β 1表达将是 通过免疫组织学、免疫电镜和信使RNA评估 研究（原位杂交和定量聚合酶链反应）。 这些测量值将与肾功能指数相关 （肾小球滤过和蛋白尿）和肾结构改变 （肾小球硬化百分比、系膜体积分数、肾小球 基底膜厚度和分裂以及皮质间质体积 分数）。 将通过比较受影响的雄性犬来检验假设2 从出生后第一个月开始接受血管紧张素抑制剂治疗 转换酶（依那普利）的狗，没有接受这样的治疗。 比较将集中在肾功能指标的变化率， 肾瘢痕形成，以及肾中的胶原和TGF-β 1表达。

DESCRIPTION (Taken directly from applicant's abstract) Alport syndrome is an inherited form of kidney disease, associated with deafness, that results from genetic abnormalities in type IV collagen, an integral component of tissue structures known as basement membranes. In most families with Alport syndrome the disease is transmitted as an X-linked dominant condition, and affected males develop kidney failure in adolescence or young adulthood. While much has been learned recently about the genetics of Alport syndrome, the mechanisms by which the disease progresses inexorably to kidney failure are not understood. There is currently no treatment for Alport kidney disease, other than renal transplantation. Kidney disease that is indistinguishable genetically, biochemically and pathologically from Alport syndrome occurs spontaneously in some dog families. These dogs provide the opportunity to test potential therapeutic interventions in Alport syndrome, and also to elucidate the pathogenesis of renal failure in this disease. The studies proposed in this application are based on the following hypotheses: (1) renal failure in Alport syndrome results from accumulation of particular collagen types in the kidney, initiated by the primary genetic defect and driven by TGF-b1; and (2) inhibition of angiotensin converting enzyme can slow the rate of progression to renal failure, by suppressing TGF-b1 activity and consequently the accumulation of collagen in the kidney. Hypothesis #1 will be tested by performing serial renal biopsies in affected male members of a dog family with hereditary nephritis (so-called "Navasota dogs"). The extent of collagen accumulation and TGF-b1 expression in these biopsies will be assessed by immunohistology, immunoelectron microscopy and messenger RNA studies (in situ hybridization and quantitative polymerase chain reaction). These measurements will be correlated with indices of renal function (glomerular filtration and proteinuria) and renal stuctural alterations (percent glomerular sclerosis, mesangial volume fraction, glomerular basement membrane thickness and splitting, and cortical interstitial volume fraction). Hypothesis #2 will be tested by comparing affected male dogs treated from the first month of life with an inhibitor of angiotensin converting enzyme (enalapril) to dogs that receive no such treatment. Comparisons will focus on the rates of change in measures of renal function, renal scarring, and collagen and TGF-b1 expression in the kidneys.