Towards Molecular Diagnostics of Glomerular Disease

在2001年5月以来的第一轮资助中，我们重点关注了TGF-β/Smad信号转导的作用， 肾小球硬化症足细胞和鼠模型中的下游转录程序， 这项更新申请的主要目标是开发和验证分子生物学技术， 用于分类和预测进展性CKD的标记，基于一组47个标记基因， 通过微阵列筛选鉴定，并且我们将其表征为基于TR的分类器和/或预测器。 在几种CKD小鼠模型中进行性肾损伤的表达值。这表示 继续我们的努力，以确定分子信号传导机制和遗传程序，介导 进行性肾脏疾病，同时，代表了一个新的转化，临床前研究的重点 开发急需的新型分子标记物，以支持临床研究和临床管理 的CKD。我们假设，这组47个候选分子标记提供了一种新的和独特的 资源的发展'诊断'和'预后'的分子分类实验和 人CKD。我们建议进行整合的转化和临床前研究，以确定和确认敏感和 用于诊断和预后进展性CKD的特异性分子标志物。具体目标：1） 鉴定并验证47个预先筛选的标记基因中的最高基因，所述标记基因a）定义 （“诊断”），基于它们的mRNA表达谱，在六种良好的疾病模型中， 表征的CKD鼠肾病模型，和B）基于它们的mRNA表达谱， 在这些模型中，CKD的离散临床相关早期或晚期阶段。2)要验证是否 这些顶级基因的mRNA表达谱实现了疾病类别的可比定义和/或 在现有的人肾活检样本中，来自原发性高血压患者的注释良好的病例中存在不同的进展阶段， FSGS、狼疮性肾炎和DNP，可从欧洲肾脏cDNA库联盟获得。.

During the first cycle of this grant since 5/2001, we have focused on the role of TGF-b/Smad signaling and downstream transcriptional programs in podocyte and murine models of glomerulosclerosis and tubulointerstitial fibrosis.The primary goals of this renewal application are to develop and validate molecular markers for classification and prediction of progressive CKD, based on a set of 47 marker genes that we identified by microarray screens, and that we characterized as classifiers and/or predictors based on tr^eir expression values in progressive renal injury in several mouse models of CKD. This represents a continuation of our efforts to define molecular signaling mechanisms and genetic programs that mediate progressive renal disease, and, at the same time, represents a new translational, preclinical researchfocus to develop much needed, novel molecular markers to support clinical investigation and clinical management of CKD. We hypothesize that the set of 47 candidate molecular markers provides a novel and unique resource for development of 'diagnostic' and 'prognostic' molecular classifications of experimental and human CKD. We propose integrated translational and preclinical studies to identify and confirm sensitive and specific molecular markers for diagnosis and for prognosis of progressive CKDs. Specific Aims: 1) To identify and validate the top genes among the set of 47 prescreened marker genes that a) define ('diagnose'), based on their mRNA expression profile, a single specific disease model among six well- characterized murine kidney disease models of CKD, and b) define, based on their mRNA expression profile, discrete clinically-relevant early or advanced stages of CKD in these models. 2) To validate whether the mRNA expression profiles of these top genes achieve comparable definitions of disease categories and/or distinct progression stages in existing human kidney biopsy samples from well-annotated cases of primary FSGS, lupus nephritis, and DNP, available in the European Renal cDNA Bank Consortium. .