Biomolecular Markers for Safe Minimization of Immunosuppression

描述(由申请人提供)：该研究的具体目标是测试以下假设：尿液细胞/外周血细胞/肾移植活检组织的信使RNA表达谱(mRNA谱)和microRNA谱(miRNA谱)可预测和诊断肾移植受者的急性排斥反应、亚临床急性排斥反应和慢性移植肾病(CAN)，这些患者随机分为低剂量或标准剂量他克莫司治疗组。具体目的1：评价随机时测量的尿细胞/外周血细胞/移植肾活检mRNA/miRNA图谱在预测(I)临床急性排斥反应、(Ii)亚临床急性排斥反应和(Iii)Can的预后价值。具体目的2：确定与随机使用标准他克莫司方案的肾移植受者相比，随机使用低他克莫司方案的同种异体肾移植受者是否表现出不同的尿细胞/外周血细胞mRNA/miRNA谱的纵向模式。具体目的3：评价尿液细胞/外周血细胞/移植肾活检mRNA/miRNA图谱对亚临床急性排斥反应(CAN)的诊断价值。这项拟议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(靶浓度：3.0~5.0 ng/ml)和标准他克莫司方案(6.0~8.0 ng/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个月接受常规肾移植活检。随机对照试验是由美国国立卫生研究院授予威尔·康奈尔大学、行业和机构基金的临床和翻译奖相结合支持的，在这项申请中，随机对照试验的执行不需要任何资金。这项mRNA/miRNA图谱研究利用了随机对照试验，拟议的研究可能导致开发非侵入性和机械信息的分子生物标记物，用于将器官移植受者的免疫抑制治疗安全降至最低。 公共卫生相关性：在器官移植受者中，免疫抑制药物的使用与过度感染、恶性肿瘤以及心血管和代谢异常有关。因此，最大限度地减少免疫抑制是器官移植的主要目标。我们建议开发基于基因的诊断测试，以指导器官移植受者将免疫抑制治疗降至最低。

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.