The severity of interstitial inflammation is known to correlate well with the severity of clinical renal disease, but the mechanisms involved in these events are poorly understood. To gain information about these pathways, this project will focus on a spontaneous, genetically-determined, model of interstitial nephritis in mice. Mice that are homozygous for the kidney disease (kd) gene on chromosome 10 spontaneously develop a form of interstitial nephritis which is usually lethal by about 20 weeks of age. A class I-restricted autoimmune reaction is directed to a tubular basement membrane antigen. In this project, the kd gene will be investigated by means of a positional cloning approach. The molecular information derived from cloning and sequencing this gene will be utilized to understand the mechanisms by which interstitial nephritis is induced.
The specific aims are (1) to identify, by genetic recombination, the specific interval on chromosome 10 within which the kd gene maps, and to investigate candidate genes for kd in the cloned interval, (2) to examine the interaction of the kd gene with other relevant genes with the C57BL/6 (B6) background, and (3) to characterize comprehensively the nephritogenic effector T cell response in diseased kd/kd mice. In this project, therefore, a unique animal model of spontaneous, chronic, progressive interstitial nephritis will be studied. The potential relevance of this project is that explication of pathways that lead to tubulointerstitial injury, at the molecular and cellular levels, could lead to the development of rational therapeutic or prophylactic interventions.
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