Post-transcriptional regulation of gene expression by microRNAs in antibody-mediated rejection

抗体介导的排斥反应中 microRNA 对基因表达的转录后调控

• 批准号: 10522285
• 负责人: Robert L Fairchild
• 金额: $ 70.11万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522285
• 关键词: Address; Affect; Allografting; Antibodies; Calcineurin inhibitor; Cells; Chronic; Clinical; Communities; Complement; Complex; Data; Disease; Event; Fibrosis; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Graft Rejection; Human; Injury; Injury to Kidney; Kidney; Kidney Failure; Kidney Transplantation; Knowledge; Lead; Maps; Mediating; Messenger RNA; MicroRNAs; Mus; Pathology; Pathway interactions; Play; Post-Transcriptional Regulation; Post-Translational Regulation; Process; Proteins; RNA; RNA-Binding Proteins; RNA-Induced Silencing Complex; Regulation; Reporting; Resources; Role; Sampling; Signal Pathway; Testing; Toxic effect; Transplantation; Untranslated RNA; allograft rejection; antibody-mediated rejection; base; clinically relevant; clinically translatable; crosslink; differential expression; digital; insight; integrin-linked kinase; interest; kidney allograft; kidney cell; member; miRNA expression profiling; mouse model; novel; prediction algorithm; prevent; renal damage; response; response to injury

Chronic antibody-mediated rejection (AMR) is a major cause of renal allograft rejection. Yet despite its clinical importance an integrated understanding of how responses to antibody and complement mediated attack are regulated by the transplanted kidney has not been established. This gap in our knowledge is due at least in part to an incomplete understanding of responses made by the kidney that result in gene regulation promote or prevent injury. MicroRNAs (miRNAs) are a class of small noncoding RNAs that regulate gene expression post-transcriptionally. miRNAs play an important role in regulating renal injury. However, the study of miRNAs in rejection and renal injury has largely been based on analysis of total cellular miRNAs that are differentially expressed during disease. This approach is problematic because it does not provide information on the mRNAs targeted by these miRNAs. To address this issue, we asked whether it is possible to isolate miRNAs and the mRNAs they are targeting in the RNA-Induced Silencing Complex (RISC) by isolating RNAs cross-linked to the RNA Binding Protein (RBP) AGO2. Using this approach we defined the first miRNA-mRNA interaction map for transplant related renal injury. These proof-of-principle studies revealed that within the miRNA-mRNA targetome it is possible to defined miRNAs and the mRNAs they target that undergo unique changes in cells undergoing injury. Pathway enrichment analysis indicated that miRNAs present in the RISC complex target mRNAs encoding proteins in pathways that may contribute to injury. Based on these studies, we hypothesize that the miRNA-mRNA targetome can be used to identify gene pathways that contribute to AMR. To test this hypothesis, we will use a clinically relevant murine model to determine the miRNA-mRNA map for AMR and use information elucidated by the targetome to examine gene pathways under regulation by miRNAs. We examine the clinical relevance of our findings by examining whether similar changes occur in human kidney transplants. These studies will provide unique insight into process that drive pathology associated with AMR, information that could be used to distinguish AMR from other types of injury, and provides a novel resource to the transplantation and wider scientific community.

慢性抗体介导的排斥反应（AMR）是同种异体移植排斥的主要原因。然而 尽管其临床重要性是对抗体的反应和 尚未建立补体介导的攻击受移植肾脏的调节。 我们所知的差距至少部分是由于对回应的不完全理解 由导致基因调节的肾脏促进或预防损伤。 microRNA（mirnas） 是一类小型非编码RNA，在转录后调节基因表达。 miRNA在调节肾脏损伤方面起着重要作用。但是，对miRNA的研究 排斥和肾脏损伤主要基于对总细胞miRNA的分析 在疾病期间差异表达。这种方法是有问题的，因为它不提供 这些miRNA针对的mRNA的信息。为了解决这个问题，我们询问是否 可以分离miRNA和它们靶向RNA诱导的沉默的mRNA 复合物（RISC）通过分离与RNA结合蛋白（RBP）AGO2的RNA分离。使用 我们定义了第一个用于移植相关肾脏损伤的miRNA-mRNA相互作用图。 这些原则证明的研究表明，在miRNA-mRNA靶标内，有可能 定义的miRNA及其靶向的mRNA，在经历细胞的独特变化 受伤。途径富集分析表明RISC复合物中存在的miRNA 在可能导致损伤的途径中编码蛋白质的mRNA。基于这些研究，我们 假设miRNA-mRNA靶体可用于鉴定基因途径 为AMR做出贡献。为了检验这一假设，我们将使用临床相关的鼠模型 确定用于AMR的miRNA-mRNA图，并使用目标群阐明的信息 检查由miRNA调节的基因途径。我们检查了我们的临床相关性 通过检查人类肾脏移植中是否发生类似变化来发现。这些研究 将提供对驱动与AMR相关的病理学的过程的独特见解，信息 可以用来区分AMR与其他类型的伤害，并为 移植和更广泛的科学界。