Biomolecular Markers for Safe Minimization of Immunosuppression

描述（由申请人提供）：具体目标是测试尿细胞/外周血细胞/肾移植活检的信使RNA表达谱（mRNA谱）和microRNA表达谱（miRNA谱）的假设，这些假设可以预测和诊断随机分配到低剂量或标准剂量他克莫司方案的肾移植受体的急性排斥反应、亚临床急性排斥反应和慢性同种异体移植肾病（CAN）。具体目标1：评估尿细胞/外周血细胞/同种异体移植活检mRNA/miRNA谱的预后作用，在随机化时测量，用于预测随后的发展(i)临床急性排斥反应；（ii）亚临床急性排斥反应和（iii） CAN。特异性目的2：确定随机分配到低他克莫司方案的肾移植受体与随机分配到标准他克莫司方案的受体相比，是否在尿细胞/外周血细胞中表现出不同的mRNA/miRNA纵向模式。特异性目的3：评估尿细胞/外周血细胞/同种异体移植活检mRNA/miRNA谱在诊断亚临床急性排斥反应或CAN中的诊断价值。该研究的研究队列将纳入160名肾移植受体，纳入我们的单中心随机对照试验（RCT），比较低他克莫司方案（目标谷水平：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个月进行肾移植活检。该RCT由美国国立卫生研究院-临床和转化奖，工业和机构基金联合支持，在本应用中不需要为RCT的表现提供资金。这项mRNA/miRNA分析研究利用了随机对照试验，提出的研究可能会导致无创和机械信息分子生物标志物的发展，以最大限度地减少器官移植受体免疫抑制治疗的安全。

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. PUBLIC HEALTH RELEVANCE: The use of immunosuppressive drugs is associated with an excess of infections, malignancy and cardiovascular and metabolic aberrations in organ graft recipients. Thus, immunosuppression minimization is a major goal in organ transplantation. We propose to develop gene-based diagnostic tests for guiding the minimization of immunosuppressive therapy in organ graft recipients.