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.
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.
|Suhre, Karsten; Schwartz, Joseph E; Sharma, Vijay K et al. (2016) Urine Metabolite Profiles Predictive of Human Kidney Allograft Status. J Am Soc Nephrol 27:626-36|
|Kannabhiran, Dinesh; Lee, John; Schwartz, Joseph E et al. (2015) Characteristics of Circulating Donor Human Leukocyte Antigen-specific Immunoglobulin G Antibodies Predictive of Acute Antibody-mediated Rejection and Kidney Allograft Failure. Transplantation 99:1156-64|
|Lee, John R; Muthukumar, Thangamani; Dadhania, Darshana et al. (2015) Gut microbiota and tacrolimus dosing in kidney transplantation. PLoS One 10:e0122399|
|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) 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|
|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|
|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|
|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|
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