We propose to undertake a comprehensive mechanistic study to establish informative biomarkers in pediatric renal transplantation, using patient clinical data and tissue (biopsy and blood) from SNS01- a randomized clinical trial of steroid-free versus steroid-based immunosuppression. This proposal outlines a strategy for integrating clinical and pathology cores from SNS01 with genomic (cDNA arrays and real-time PCR) and immunopathology (core biopsies and tissue microarrays) cores, the latter two cores to be generated by this proposal.
The aims of this study are fourfold. (i) To develop diagnostic biomarkers by DNA microarray analysis, in tissue and blood for stable transplants, acute rejection (AR) and chronic allograft nephropathy (CAN). (ii) To detect differences in these graft states in steroid-free and steroid-based immunosuppression. (iii)To correlate the expression of selected highly differentiated genes in tissue and blood, using real-time PCR, to establish non-invasive blood markers for graft surveillance, AR diagnosis, classification, and stratification of AR therapy and outcome. (iv) To use immunohistochemistry analysis on core patient biopsies and tissue microarrays to correlate gene expression data with cellular infiltration phenotypes, density and activation in AR, CAN and normal post-transplant kidneys, in steroid-free and steroid-based immunosuppression. These studies are expected to facilitate the definition of immunological and cellular mechanisms underlying stable transplants and different forms of renal allograft dysfunction, different types of immunosuppression (with and without steroids), and generate clinical tools for non-invasive graft monitoring, as well as graft therapeutic and risk stratification. The genomic and tissue microarray databases will be made publicly available for the academic community to facilitate future large-scale collaborative studies. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI061739-04
Application #
7233125
Study Section
Special Emphasis Panel (ZRG1-SSS-J (04))
Program Officer
Kraemer, Kristy A
Project Start
2004-06-01
Project End
2009-05-31
Budget Start
2007-06-01
Budget End
2009-05-31
Support Year
4
Fiscal Year
2007
Total Cost
$379,272
Indirect Cost
Name
Stanford University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Sigdel, Tara K; Gao, Yuqian; He, Jintang et al. (2016) Mining the human urine proteome for monitoring renal transplant injury. Kidney Int 89:1244-52
Vitalone, Matthew J; Sigdel, Tara K; Salomonis, Nathan et al. (2015) Transcriptional Perturbations in Graft Rejection. Transplantation 99:1882-93
Roedder, Silke; Li, Li; Alonso, Michael N et al. (2015) A Three-Gene Assay for Monitoring Immune Quiescence in Kidney Transplantation. J Am Soc Nephrol 26:2042-53
Sigdel, Tara K; Sarwal, Minnie M (2013) Moving beyond HLA: a review of nHLA antibodies in organ transplantation. Hum Immunol 74:1486-90
Sigdel, Tara K; Vitalone, Matthew J; Tran, Tim Q et al. (2013) A rapid noninvasive assay for the detection of renal transplant injury. Transplantation 96:97-101
Lee, Sangho; Naesens, Maarten; Li, Li et al. (2012) Stanniocalcin supports the functional adaptation of adult-sized kidneys transplanted into the pediatric recipients. Transplantation 93:1130-5
Li, L; Khatri, P; Sigdel, T K et al. (2012) A peripheral blood diagnostic test for acute rejection in renal transplantation. Am J Transplant 12:2710-8
Sigdel, Tara K; Woo, Sang Hoon; Dai, Hong et al. (2011) Profiling of autoantibodies in IgA nephropathy, an integrative antibiomics approach. Clin J Am Soc Nephrol 6:2775-84
Naesens, Maarten; Khatri, Purvesh; Li, Li et al. (2011) Progressive histological damage in renal allografts is associated with expression of innate and adaptive immunity genes. Kidney Int 80:1364-76
Vitalone, Matthew J; Naesens, Maarten; Sigdel, Tara et al. (2011) The dual role of epithelial-to-mesenchymal transition in chronic allograft injury in pediatric renal transplantation. Transplantation 92:787-95

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