Biomolecular Markers for Safe Minimization of Immunosuppression

描述（申请人提供）：具体目标是检验信使RNA表达谱的假设，（mRNA谱）和microRNA表达谱尿细胞/外周血细胞/肾同种异体移植物活组织检查的miRNA谱（miRNA谱）是急性排斥、亚临床急性排斥，和慢性移植物肾病（CAN）的肾移植受者随机分配到低剂量或标准剂量他克莫司方案。具体目标1：评价随机化时测量的尿细胞/外周血细胞/同种异体移植物活检mRNA/miRNA谱预测（i）临床急性排斥反应;（ii）亚临床急性排斥反应和（iii）CAN后续发展的预后效用。具体目标二：确定与随机分配至标准他克莫司方案的肾移植受者相比，随机分配至低剂量他克莫司方案的肾移植受者在尿细胞/外周血细胞中是否表现出不同的mRNA/miRNA谱的纵向模式。具体目标3：评估尿细胞/外周血细胞/同种异体移植物活检mRNA/miRNA谱对亚临床急性排斥反应或CAN的诊断效用。本研究的研究队列将包括160名肾移植受者，他们参加了我们的单中心随机对照试验（RCT），比较了低他克莫司方案（目标谷浓度：3.0 - 5.0ng/ml）和标准他克莫司方案（6.0-8.0ng/ml）。随机化将在移植后3个月进行，受试者将在随机化时以及随机化后12个月和33个月接受方案肾移植物活检。该RCT得到了授予Weill Cornell的NIH临床和转化奖、行业和机构基金的支持，在本申请中，不需要为RCT的执行提供资金。这项mRNA/miRNA分析研究利用了RCT，拟议的研究可能会导致开发非侵入性和机械信息分子生物标志物，用于器官移植受者安全地最大限度地减少免疫抑制治疗。

DESCRIPTION (provided by applicant): The specific goal is to test the hypotheses that messenger RNA expression profiles (mRNA profiles) and microRNA expression profiles (miRNA profiles) of urinary cells/peripheral blood cells/ renal allograft biopsies are predictive and diagnostic of acute rejection, subclinical acute rejection, and chronic allograft nephropathy (CAN) in renal allograft recipients randomized to either a low dose or a standard dose tacrolimus regimen. Specific Aim 1: To evaluate the prognostic utility of urinary cell/peripheral blood cell/allograft biopsy mRNA/miRNA profiles, measured at the time of randomization, for predicting the subsequent development of (i) clinical acute rejection; (ii) subclinical acute rejection and (iii) CAN. Specific Aim 2: To determine whether renal allograft recipients randomized to a low tacrolimus regimen exhibit a different longitudinal pattern of mRNA/miRNA profiles in urinary cells/peripheral blood cells compared to recipients randomized to a standard tacrolimus regimen. Specific Aim 3: To evaluate the diagnostic utility of urinary cell/peripheral blood cell/ allograft biopsy mRNA/miRNA profiles for the diagnosis of subclinical acute rejection or CAN. The study cohort for the proposed study will be 160 renal allograft recipients enrolled in our single center randomized controlled trial (RCT) comparing a low tacrolimus regimen (target trough level: 3.0 to 5.0ng/ml) with a standard tacrolimus regimen (6.0-8.0ng/ml). Randomization will occur at 3 months post-transplantation and the subjects will undergo protocol renal allograft biopsy at the time of randomization and at 12 and 33 months post-randomization. The RCT is supported by the combination of a NIH- Clinical and translational award to Weill Cornell, industry, and institutional funds and no funds are requested for the performance of RCT in this application. This mRNA/miRNA profiling study leverages the RCT and the proposed research may lead to the development of noninvasive and mechanistically informative molecular biomarkers for the safe minimization of immunosuppressive therapy in organ graft recipients.