Towards Molecular Diagnostics of Glomerular Disease

在自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信号转导和 足细胞和小鼠肾小球硬化模型中的下游转录程序 肾小管间质纤维化：这种更新应用的主要目标是开发和验证分子 基于一组47个标记基因的进展性慢性肾脏病的分类和预测标记 由微阵列筛选识别，并且我们基于TR^EIR将其描述为分类器和/或预测器 慢性肾脏病小鼠模型进行性肾损伤的表达价值。这表示一个 我们继续努力定义分子信号机制和基因程序 进行性肾病，同时也代表了一个新的翻译的，临床前的研究重点 开发急需的新型分子标记以支持临床研究和临床管理 对CKD的研究。我们假设这组47个候选分子标记提供了一个新颖而独特的 用于开发实验性和预见性分子分类的资源 人类CKD。我们建议进行综合的翻译和临床前研究，以确定和确认敏感和 进展性角化病诊断和预后的特异性分子标志物。具体目标：1) 在47个预先筛选的标记基因集合中识别和验证最顶端的基因 (‘诊断’)，基于他们的mRNA表达谱，在六个井中建立单一的特定疾病模型。 CKD的特征性小鼠肾脏疾病模型，以及b)基于其mRNA表达谱定义， 在这些模型中，离散的临床相关的早期或晚期CKD。2)验证是否 这些顶级基因的mRNA表达谱实现了疾病类别和/或 现有人类肾脏活检样本中的不同进展阶段来自有良好注解的原发病例 FSGS、狼疮性肾炎和DNP，可在欧洲肾脏cDNA银行联盟获得。。

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. .