Kollagengenregulation in Patienten mit progressiver Organfibrose auf dem Boden einer diabetischen Nephropathie oder IgA Nephritis

Inflammatory and non-inflammatory organ diseases are often accompanied by destruction of the tissue architecture and formation of scar tissue. Progressive loss of organ function ensues, in the field of nephrology end-stage renal failure may develop. It remains unclear why subgroups of patients are prone to scar tissue accumulation. In this project the collagen metabolism and underlying regulatory mechanisms will be analyzed in diabetics, from which 30-40% will develop nephropathy over time, and in patients with biopsy-proven IgA nephritis that have a 30% chance of progressive disease. A profile of the ECM composition, especially of fibrillary type I and III collagens, will be obtained in patient cohorts with progressive organ fibrosis (200 patients each: type I & II diabetes, IgA nephritis) and compared to non-progressive disease. As preliminary results in these patients indicate a generalized wound healing disturbance due to a polymorphic poly-A/T tract within the type III collagen gene, that is functionally involved in gene transcription, our primary goal will be to test whether this genetic alteration is predictive of progressive disease. Binding of transcription factors to or adjacent to this sequence element will be analyzed in model cell systems (fibroblasts, tubular cells, mesangial cells), combined with a search for additional cis-regulatory elements. With identification of binding activities we will evaluate specific intervention(s) by means of small interfering RNA. The insights obtained may help in predicting occurrence and natural course of organ fibrosis and provide a rationale for specific intervention.