The overall gear is to build on the progress we have made and to leverage our recent ground-breaking advances in gene expression profiling technologies.
SPECIFIC AIM 1 : To perform broad, unbiased, deep sequencing of urine from kidney graft recipients undergoing surveillance and/or for-cause biopsies and discover new mRNA and miRNA signatures diagnostic and prognostic of acute rejection (AR), subclinical AR (SAR) and chronic allograft nephropathy (CAN) (SA. IA) and develop novel parameters for characterizing the in-vivo immune status of kidney graft recipients and the adequacy of their immunosuppressive therapy (SA. IB).
SPECIFIC AIM 2 : To test whether a previously discovered 3-gene signature of ISS-normalized C D 3 E and IP-10 mRNA, measured in sequential urine specimens, predicts the subsequent development of AR and SAR (SA. 2A);to test whether a previously discovered 4-gene signature of vimentin, NKCC2, E-cadherin and 18S rRNA, measured in sequential urine specimens, predicts the subsequent development of CAN (SA. 2B);and to test whether a miRNA panel comprised of miR-21, -21*, -30a-3p, -100;-142-3p/5p, -192, -194, - 200b, -222;and -223, measured in sequential urine specimens, predicts the subsequent development of AR, SAR and CAN (SA. 2C).
SPECIFIC AIM 3 : To test whether the previously discovered signatures and the miRNA panel, measured in sequential urine specimens, are associated with the type of induction therapy (T cell depleting antibody induction vs. anti-IL-2 receptor mABs induction) and with maintenance . immunosuppressive therapy (tacrolimus vs. no tacrolimus). Messenger RNAs and microRNAs, discovered by sequencing to be associated with AR, SAR and CAN (SA. 1) and measured in sequential samples (SA. 2), will be incorporated in statistical analyses to determine: (1) whether the previously identified signatures can be further optimized to improve their diagnostic and prognostic utility;and (2) whether the previously identified signatures can be further refined to improve their ability to track the influence of induction therapy and maintenance therapy on the immune status of kidney graft recipients.

Public Health Relevance

An excess of immunosuppressive drugs is associated with infections, malignancy and cardiovascular and metabolic aberrations in organ graft recipients whereas inadequate immunosuppression is associated with allograft rejection. Thus, immunosuppression optimization is a major goal in organ transplantation. We propose to develop gene-based prognostic and diagnostic tests for characterizing the in-vivo immune status of kidney graft recipients and for monitoring the adenuacv of their immunosuppressive therapy.

Agency
National Institute of Health (NIH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37AI051652-11
Application #
8634830
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Hayes, Deborah
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10065
Muthukumar, Thangamani; Lee, John R; Dadhania, Darshana M et al. (2014) Allograft rejection and tubulointerstitial fibrosis in human kidney allografts: interrogation by urinary cell mRNA profiling. Transplant Rev (Orlando) 28:145-54
Lee, John R; Muthukumar, Thangamani; Dadhania, Darshana et al. (2014) Urinary cell mRNA profiles predictive of human kidney allograft status. Immunol Rev 258:218-40
Lee, John R; Muthukumar, Thangamani; Dadhania, Darshana et al. (2014) Gut microbial community structure and complications after kidney transplantation: a pilot study. Transplantation 98:697-705
Matignon, Marie; Ding, Ruchuang; Dadhania, Darshana M et al. (2014) Urinary cell mRNA profiles and differential diagnosis of acute kidney graft dysfunction. J Am Soc Nephrol 25:1586-97
Lee, John R; Dadhania, Darshana; August, Phyllis et al. (2014) Circulating levels of 25-hydroxyvitamin D and acute cellular rejection in kidney allograft recipients. Transplantation 98:292-9
Suthanthiran, Manikkam; Schwartz, Joseph E; Ding, Ruchuang et al. (2013) Urinary-cell mRNA profile and acute cellular rejection in kidney allografts. N Engl J Med 369:20-31
Muthukumar, Thangamani; Afaneh, Cheguevara; Ding, Ruchuang et al. (2013) HIV-infected kidney graft recipients managed with an early corticosteroid withdrawal protocol: clinical outcomes and messenger RNA profiles. Transplantation 95:711-20
Dadhania, Darshana; Snopkowski, Catherine; Muthukumar, Thangamani et al. (2013) Noninvasive prognostication of polyomavirus BK virus-associated nephropathy. Transplantation 96:131-8
Dadhania, Darshana; Snopkowski, Catherine; Ding, Ruchuang et al. (2010) Validation of noninvasive diagnosis of BK virus nephropathy and identification of prognostic biomarkers. Transplantation 90:189-97
Afaneh, Cheguevara; Muthukumar, Thangamani; Lubetzky, Michelle et al. (2010) Urinary cell levels of mRNA for OX40, OX40L, PD-1, PD-L1, or PD-L2 and acute rejection of human renal allografts. Transplantation 90:1381-7

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