Cytomegalovirus and Chronic Renal Allograft Rejection

DESCRIPTION (provided by applicant): Dr. Shimamura is a pediatric infectious diseases specialist whose career goal is to establish a molecular and translational program in solid organ transplant infectious diseases, focusing upon viral infections in transplant recipients. She plans to pursue clinician-scientist training under the tutelage of Dr. William J. Britt, noted herpesvirologist, and Dr. Mark Benfield, transplant immunologist and national leader in pediatric renal transplant research. Formal molecular biology coursework and clinical transplant infectious diseases training outlined in this proposal will provide her with the educational foundation for future research in molecular virology, transplant infections, and patient-based translational research to determine causes and treatments for infections related to solid organ transplantation. Dr. Shimamura is based at the University of Alabama-Birmingham, which has a nationally recognized solid organ transplantation program. Dr. Shimamura studies human cytomegalovirus (HCMV), which has been linked epidemiologically to chronic renal allograft rejection and long-term graft loss, but the pathogenesis remains poorly understood. She has identified a novel mechanism by which HCMV may promote renal fibrosis via activation of transforming growth factor-[unreadable]1 (TGF-[unreadable]1), a potent pro-fibrotic cytokine found in renal allografts during chronic rejection. TGF-[unreadable]1 triggered matrix metalloprotease (MMP) production is also enhanced by HCMV infection of renal tubular cells. These data implicate a positive feedback loop between TGF-[unreadable]1, MMPs, and HCMV promoting fibrosis contributing to renal allograft dysfunction. This study will: (1) characterize the MMP-driven mechanism by which HCMV-infected cells activate TGF-[unreadable]1;(2) determine the HCMV gene(s) promoting TGF-[unreadable]1 activation;and (3) establish an in vivo murine model for CMV enhanced chronic renal allograft fibrosis. The long-term goal is to develop diagnostic and therapeutic strategies to prevent or abrogate CMV related renal fibrosis during chronic renal allograft rejection, thus preserving graft function in HCMV infected patients with chronic renal allograft rejection. Public Health Relevance: This research will provide insight into the molecular pathogenesis of cytomegalovirus contributions to renal fibrosis during chronic renal allograft rejection. Such studies will assist in development of new diagnostic strategies and treatments against chronic rejection to prevent long-term allograft loss in kidney transplant recipients, avoiding the cost and morbidity of long-term dialysis or re-transplantation in these patients.