The candidate's previous experience in the laboratory has provided him with an understanding of immunological processes in renal diseases and transplantation. This proposal under the mentorship of Drs. William E. Hannon and Terry B. Strom is designed to advance applicant's training in the application of immunological studies to SRNS. Moreover, the environment within the Clinical Research Core Program Office will educate and enable him to develop into an independent clinical investigator. The steroid resistant nature of SRNS warrants study of factors that underlie steroid resistance. Steroids suppress inflammatory and other nuclear factor kappa B (NF-kB)-dependent processes by inducing expression of IkB alpha (IkBa), which inhibits activation of NF-kB. Stimuli which activate NF-kB include the T lymphocyte co-stimulatory pathways (CD28/B7, CD40/CD154), and tumor necrosis factor alpha (TNFa). The applicant has shown: 1) that patients with SRNS demonstrate attenuated intra-renal expression of IkBa in response to steroid therapy; 2) increased intra-graft expression of NF-kB:IkBa ratio in post-transplant recurrent SRNS and acute allograft rejection; and 3) that NF-kB expression in circulating leukocytes is predictive of intra- renal and intra-graft NF-kB expression. The central hypothesis of this proposal is that steroid-resistance in SRNS is a manifestation of sustained NF-kB activation secondary to a circulating stimulus. The hypothesis that SRNS is a systemic disorder resulting in a kidney-specific disease is supported by: 1) the immediate recurrence of SRNS following transplantation; and 2) evidence of circulating factors in SRNS that cause proteinuria and conformational changes in the glomerular vasculature. The objectives are to define perturbations, cell sources, and circulating triggers of NF-kB expression in SRNS.
The specific aims of this proposal are: 1) to determine the magnitude of expression of NF-kB sub-units in SRNS; 2) to determine the specific cell phenotypes which exhibit perturbed NF-kB expression in SRNS; 3) to measure circulating TNFa as a potential trigger of NF-kB activation in SRNS; and 4) to measure co-stimulatory pathways as potential triggers of NF-kB in SRNS. This research proposal is unique in that it involves a detailed analysis of circulating immunological factors that may result in a kidney specific disease. These studies may provide insight and guidance for the development of markers of steroid resistance as well as novel therapies for SRNS.
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