Because chronic renal transplant rejection is the leading cause of late renal transplant failure and because current """"""""immunotherapy"""""""" has no beneficial effect, we propose to begin to investigate several key pathophysiologic mechanisms and selected tissue responses in a rat model of chronic renal allograft rejection.
the specific aims of this grant are: A. To test the hypothesis that non-immunologic mechanisms play a critical role in the progression of renal injury in experimental chronic renal transplant rejection. B. To examine the tissue response to injury in chronic renal transplant rejection. In Part A three non-immunologic mechanisms will be studied: renal hemodynamics, renal ammoniagenesis, and oxidative stress. These factors have been proven to play roles in the progression of experimental non-transplant renal disease. As well, in the renal hemodynamic section, the role of two other allied mediators of injury, renal growth and the renin-angiotensin system will be studied. The studies proposed in this first section of the grant will also address therapeutic aspects of chronic rejection by examining the following therapies: dietary protein restriction, converting enzyme inhibition, dietary acid reduction, free radical scavengers all of which have demonstrated beneficial effects in experimental non-transplant renal disease. The effects of these therapies on non-immunologic mechanisms of progression will be emphasized. Part B of the grant will focus on the tissue response to injury in chronic renal transplant rejection. The first hypothesis to be tested is that platelet derived growth factor (PDGF), which has been implicated in smooth muscle hyperplasia and in initiating fibrosis, or fibroblast growth factor (FGF), which is also involved in the fibrotic response, play a role in the vascular hyperplasia and fibrosis which are seen in chronic renal transplant rejection. The second hypothesis is that altered expression of the collagen genes which are involved in renal scarring are altered in chronic rejection. Finally the third hypothesis is that clusterin, a protein which is highly induced in a variety of renal injury states and which is thought to play a role in cell death, is involved in the renal injury response in chronic rejection. By gaining insight into the mechanisms responsible for, and the tissue responses to chronic rejection, the framework for understanding and intervening in this increasingly common renal transplant problem should become possible.

Project Start
Project End
Budget Start
Budget End
Support Year
29
Fiscal Year
1996
Total Cost
Indirect Cost
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