Towards Molecular Diagnostics of Glomerular Disease

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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. .