Towards Molecular Diagnostics of Glomerular Disease

描述(由申请人提供)：自2001年5月以来的第一轮赠款中，我们重点研究了转化生长因子-b/Smad信号和下游转录程序在足细胞和小鼠肾小球硬化和肾小管间质纤维化模型中的作用。这一新应用的主要目标是开发和验证用于进展性CKD分类和预测的分子标记，基于我们通过微阵列筛选识别的47个标记基因集，以及我们在几种CKD小鼠模型中基于TR^EIR表达值作为分类器和/或预测者的特征。这代表了我们继续努力定义介导进行性肾脏疾病的分子信号机制和遗传程序，同时也代表了一个新的翻译、临床前研究重点，以开发急需的新的分子标记，以支持CKD的临床研究和临床管理。我们假设这组47个候选分子标记为发展实验性和人类慢性肾脏病的“诊断”和“预测”分子分类提供了一个新的和独特的资源。我们建议进行综合的翻译和临床前研究，以确定和确认用于进展性角化病诊断和预后的敏感和特异的分子标志物。具体目的：1)在47个预先筛选的标记基因中识别和验证顶级基因，a)基于它们的mRNA表达谱，定义(‘诊断’)6个具有良好特征的CKD小鼠肾脏疾病模型中的单个特定疾病模型，以及b)根据它们的mRNA表达谱，在这些模型中定义与临床相关的早期或晚期CKD。2)验证这些顶级基因的mRNA表达谱是否能够在现有的人类肾脏活检样本中实现疾病类别和/或不同进展阶段的可比定义，这些样本来自欧洲肾脏cDNA Bank联合会提供的注释良好的原发性FSGS、狼疮性肾炎和DNP病例。

DESCRIPTION (provided by applicant): 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 research focus 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.