Despite recent reductions in the incidence of acute rejection, chronic allograft nephropathy and immunosuppressive drug side effects are still major causes of graft loss and patient morbidity. In this context, it is essential to advance our understanding of the immune response and the responses of the transplanted organ to both immune and non-immune injury mechanisms. Analysis of gene expression is one means to identify molecular pathways involved in transplantation biology. The objective of Project 1 is to use high-density microarray technology to measure differential gene expression in kidney biopsies and peripheral blood of patients with well-defined phenotypes: acute rejection, chronic allograft nephropathy and patients biopsied by protocol at 12 to 24 months with well-functioning kidney transplants. Our preliminary data based on studies of almost 100 subjects demonstrates characteristic gene expression profiles in biopsies and peripheral blood lymphocytes that correlate with transplant immunosuppression as welt as with acute rejection. Using statistical analysis of individual gene expression signals followed by hierarchical clustering and class prediction analysis we can demonstrate significant differences in the gene profiles of biopsies and PBL that define these clinical groups. Our first Specific Aim is to determine the gene expression profiles in transplant biopsies and PBL of patients in 3 well-established clinical classes. Successful completion of this Aim will create a comprehensive, statistically robust data set for gene expression profiles of both transplant biopsies and PBL including many presently unknown genes that can be correlated with clinical events following kidney transplantation. Our second Specific Aim is to establish the patterns for individual gene expression correlated with clinical events and outcomes. Successful completion of this Aim will define candidate gene sets that can be integrated with the parallel studies ofproteomics (Project 2) and complex trait genetics (Project 3). We will use in silica tools to identify gene functions and connections that reveal novel pathways in transplant biology particularly the response of the donor kidney to transplantation in the context of tissue injury, repair and chronic allograft nephropathy.
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