RENAL FAILURE IN HEREDITARY NEPHRITIS--GENESIS & THERAPY

描述(直接取自申请人的摘要) 阿尔波特综合征是一种遗传性肾脏疾病，与 耳聋，是由IV型胶原基因异常引起的 组织结构的组成部分，称为基底膜。在……里面 大多数患有Alport综合征的家庭疾病是以X连锁的方式传播的 优势状态，受影响的男性在青春期发展为肾衰竭 或者是年轻的成年人。虽然最近在遗传学方面已经学到了很多 阿尔波特综合征，疾病进展的机制 不可抗拒的肾衰竭也不为人所知。目前没有 治疗Alport肾脏疾病，肾移植除外。 一种在遗传、生化和其他方面无法区分的肾病 从病理上讲，阿尔波特综合征在一些狗身上自发发生 家人。这些狗提供了测试潜在治疗方法的机会 对Alport综合征的干预，并阐明其发病机制 这种疾病中的肾功能衰竭。本申请中建议的研究包括 基于以下假设：(1)Alport综合征的肾功能衰竭 结果是肾脏中特定类型的胶原蛋白积聚， 由原发遗传缺陷启动并由转化生长因子-β1驱动；和(2) 抑制血管紧张素转换酶可减缓进展速度 通过抑制转化生长因子-β1的活性从而导致肾功能衰竭 肾脏中的胶原蛋白积聚。假设1将通过以下方式进行检验 对受影响的一只狗家族的雄性成员进行连续肾脏活检 患有遗传性肾炎(所谓的“纳瓦索塔犬”)。其影响范围 这些活检组织中的胶原堆积和转化生长因子-β1的表达 通过免疫组织学、免疫电子显微镜和信使RNA进行评估 研究(原位杂交和定量聚合酶链式反应)。 这些测量将与肾功能指标相关联。 (肾小球滤过和蛋白尿)和肾脏结构改变 (肾小球硬化百分比，系膜体积分数，肾小球 基底膜厚度和裂开以及皮质间质体积 分数)。假设2将通过比较受影响的公狗来检验 从出生后第一个月开始服用血管紧张素抑制剂 将酶(依那普利)转化为未接受此类治疗的狗。 比较将集中在肾功能指标的变化率上， 肾脏瘢痕形成，肾脏胶原和转化生长因子-β1的表达。

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.