MicroRNAs as biomarkers for acute graft-versus-host disease

描述（由申请人提供）：急性移植物抗宿主病（aGVHD）是同种异体造血干细胞移植常见的致命并发症，供体T细胞破坏HLA不匹配的宿主组织。尽管最近取得了进展，aGVHD仍然是一个主要的临床问题，强调需要进一步阐明其机制，然后开发新的治疗策略。与此相辅相成的是，建立用于诊断和预后的血液aGVHD生物标志物将有助于患者分层接受更积极的初始治疗。近年来，血浆蛋白生物标志物已被发现并证实可用于aGVHD的诊断和预后。虽然这些发现是改善aGVHD诊断和预后评估的重要一步，但也存在一些缺点，例如需要对靶标具有所需亲和力和特异性的高亲和力质量抗体。我们的研究小组最近发现miR-155在aGVHD中起着关键的调节作用。值得注意的是，我们发现miR-155在aGVHD小鼠和患者的血清中也上调了表达。基于这一事实，我们假设miR-155血清水平可能是aGVHD诊断的一个标志物，它可以预测aGVHD的发生和严重程度。此外，由于我们最初的研究发现了几种miRNAs在aGVHD患者器官的供体T细胞中上调，我们推断其他miRNAs可能在aGVHD患者的血清中表达，可能提供潜在的诊断和预后信息。因此，本项目的总体目标是扩大对aGVHD mirna生物标志物的搜索，验证候选mirna并确定其预后意义。因此，我们建议通过在两个独立的患者队列（发现和验证队列）中测量血清miR-155表达水平，研究人类血清miR-155表达水平是否在临床aGVHD发病前升高，以及是否与异体干细胞移植受体aGVHD临床诊断、严重程度和预后相关，来解决这些研究问题。接下来，我们将在临床怀疑aGVHD的同种异体受体中进行血清整体microRNA分析，以鉴定和验证与aGVHD临床诊断和严重程度相关的其他microRNA。为了实现这些目标，我们建议使用从骨髓移植临床试验网络（BMT CTN）协议0101研究中获得的同种异体造血干细胞患者的血清样本，这些样本目前储存在NHLBI生物标本库（NHLBI Biorepository）中。这些结果将在俄勒冈州立大学获得的同种异体造血干细胞移植患者的验证队列中得到证实。如果目标实现，该研究将提高我们目前关于血清mirna在该疾病中的作用的科学知识，并提供一种新的生物标志物。

DESCRIPTION (provided by applicant): Acute Graft-versus-host disease (aGVHD) is a frequent and lethal complication of allogeneic hematopoietic stem cell transplantation in which donor T cells destroy HLA mismatched host tissues. Despite recent advances, aGVHD still remains a major clinical problem, underscoring the need to elucidate further its mechanisms to then develop novel therapeutic strategies. Complementary to this, establishing a blood aGVHD biomarker for diagnosis and prognosis will be relevant to stratify patients to more aggressive initial treatments. Recently plasma protein biomarkers for diagnosis and prognosis of aGVHD have been discovered and validated. While these discoveries represent an important step towards improving aGVHD diagnosis and prognosis assessment, there are some drawbacks such as the need for high affinity quality antibodies with the required affinity and specificity fo the target. Our group recently discovered that miR-155 plays a critical regulatory role in aGVHD. Remarkably, we found that miR-155 expression is up-regulated as well in the serum of mice and patients with aGVHD. Based on this fact, we hypothesized that miR-155 serum levels could be a marker for aGVHD diagnosis and it could predict the occurrence and severity of aGVHD. Furthermore, since our initial studies identified several miRNAs upregulated in donor T cells from organs with aGVHD, we reasoned that is likely that other miRNAs could be expressed in the serum of patients with aGVHD that could potentially provide diagnostic and prognostic information. Thus, the overall objective of this project is to expand the search for aGVHD miRNAs biomarkers, to validate candidate miRNAs and establish their prognostic significance. Therefore, here we propose to address these research questions by investigating whether human serum miR-155 expression levels increase before the onset of clinical aGVHD and whether correlate with aGVHD clinical diagnosis, severity and prognosis in allogeneic stem cell transplants recipients by measuring serum miR-155 expression levels in two independent cohort of patients (discovery and validation cohorts). Next we will intent to identify and validate other microRNAs that are associated with aGVHD clinical diagnosis and severity by performing serum global microRNA analysis in allogeneic recipients at the time of clinical suspicion of aGVHD. To achieve these goals we are proposing to use serum samples from allogeneic HSCT patients obtained from bone marrow transplant clinical trial network (BMT CTN) Protocol 0101 study, which are currently stored in the NHLBI Biologic Specimen Repository (NHLBI Biorepository). These results will then been confirmed in validation cohort of allogeneic HSCT patients obtained from OSU. If aims achieved, the proposed study will improve our current scientific knowledge about the role of serum miRNAs in this disease and provide with a novel biomarker.