The overall objective of this project is to develop a noninvasive diagnostic test that is predictive, diagnostic and prognostic of human renal allograft rejection. In an exploratory study, we found that the levels of expression of mRNA encoding cytotoxic proteins perforin and granzyme B in urinary cells of renal allograft recipients are diagnostic of acute rejection of human renal allografts. We now propose to further develop and refine the noninvasive diagnosis of acute rejection.
The specific aims of this investigation are:
Specific aim 1. To test the hypothesis that mRNA profiling of urinary cells is diagnostic of subclinical rejection. We will measure mRNA for perforin, granzyme B, fas ligand, CD3 epsilon chain (CD3), interferon gamma (IFN-gamma), and interleukin-15 (IL-15) in urine specimens obtained at the time of protocol biopsies and determine the sensitivity and specificity of mRNA levels in diagnosing subclinical rejection.
Specific aim 2. To test the hypotheses that: a) alterations in mRNA levels in sequential urine specimens predict the development of acute rejection, and b) mRNA profiles predict renal allograft function. We will determine whether acute rejection episodes can be predicted by alterations in mRNA levels measured in sequential urine specimens. In addition to mRNAs listed under Specific Aim 1, we will measure level of expression of mRNA for Bcl-2, A20, hemeoxygenase-1 (HO1), Bax, and transforming growth factor-beta1 (TGF-beta1) in urinary cells and test the hypothesis that the mRNA levels predict renal allograft function.
Specific aim 3. To investigate whether mRNA profiles of urinary cells are diagnostic of clinical acute rejection and to determine whether mRNA profiles are prognostic with respect to responsiveness to antirejection therapy with corticosteroids, and in identifying allografts at risk for progressive decline in renal function. We will determine whether the level of expression of mRNA for granzyme B, perforin, and CD3, IFN-gamma and IL-15 are diagnostic of clinical acute rejection and are higher in those with corticosteroid resistant acute rejections compared to corticosteroid sensitive acute rejections. We will also determine whether hyperexpression of mRNA for cytotoxic proteins and for Bax and TGF-beta1 is associated with graft functional decline whereas lack of hyperexpression of mRNA for cytotoxic proteins, Bax and TGF-beta1 and hyperexpression of mRNA for Bcl-2, A20 and HO1 is associated with stable renal function.
| Thareja, Gaurav; Yang, Hua; Hayat, Shahina et al. (2018) Single nucleotide variant counts computed from RNA sequencing and cellular traffic into human kidney allografts. Am J Transplant 18:2429-2442 |
| Moskowitz-Kassai, Eliza; Mackelaite, Lina; Chen, Jun et al. (2012) Excretion of anti-angiogenic proteins in patients with chronic allograft dysfunction. Nephrol Dial Transplant 27:494-7 |
| Hartono, Choli; Muthukumar, Thangamani; Suthanthiran, Manikkam (2010) Noninvasive diagnosis of acute rejection of renal allografts. Curr Opin Organ Transplant 15:35-41 |
| 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 |
| Anglicheau, Dany; Sharma, Vijay K; Ding, Ruchuang et al. (2009) MicroRNA expression profiles predictive of human renal allograft status. Proc Natl Acad Sci U S A 106:5330-5 |
| Anglicheau, Dany; Suthanthiran, Manikkam (2008) Noninvasive prediction of organ graft rejection and outcome using gene expression patterns. Transplantation 86:192-9 |
| Muthukumar, Thangamani; Dadhania, Darshana; Ding, Ruchuang et al. (2005) Messenger RNA for FOXP3 in the urine of renal-allograft recipients. N Engl J Med 353:2342-51 |
| Tatapudi, Ravi Raju; Muthukumar, Thangamani; Dadhania, Darshana et al. (2004) Noninvasive detection of renal allograft inflammation by measurements of mRNA for IP-10 and CXCR3 in urine. Kidney Int 65:2390-7 |
| Hartono, Choli; Dadhania, Darshana; Suthanthiran, Manikkam (2004) Noninvasive diagnosis of acute rejection of solid organ transplants. Front Biosci 9:145-53 |
| Muthukumar, Thangamani; Ding, Ruchuang; Dadhania, Darshana et al. (2003) Serine proteinase inhibitor-9, an endogenous blocker of granzyme B/perforin lytic pathway, is hyperexpressed during acute rejection of renal allografts. Transplantation 75:1565-70 |
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