Dissecting the role of dynamic epigenome prompting pathways leading to kidney allograft fibrosis

晚期移植物丢失仍然是肾移植(KT)后的一个主要问题，主要是由于死亡。 有功能正常的移植物和固有的移植物衰竭(或慢性移植物功能障碍(CAD))。CAD仍然是一种 随着时间的推移，移植肾磨损的主要原因，导致终末期肾脏疾病护理的重新机构。计算机辅助设计是 被许多人认为是慢性肾脏疾病(CKD)的变种，既有免疫性的，也有非免疫性的 间质纤维化、肾小管萎缩(IFTA)和进行性肾小管丢失的发生机制 移植物的功能。移植物早期纤维化的发展预示着移植物功能的晚期。研究早期因素 参与肾脏纤维化的进展，我们建立了298名KT患者的纵向随访队列， 同种异体肾移植的序贯基因组取样。配对的外周样品也可供选择。利用这一点 A)早期移植物损伤的分子激活剂。 肾移植进展为纤维化的受者与最初的损伤原因无关，b)有 进展为CRAD患者的同种异体移植物中持续的促炎和氧化应激倾向 供体肾组织中特异性DNA甲基化(DNaM)模式与短期和长期结果相关 同种异体肾移植后，行IFTA检查后，dNaM形态有明显改变。 移植肾功能和移植肾组织学和移植肾功能(NFA)正常的移植肾活检2年后下降 KT后，和e)初步数据表明，特定的上游表观遗传修饰与 具有与免疫反应增强和同种异体移植修复受损相关的典型基因途径。一个 将使用独立队列2(多中心、五个机构)进行验证和复制。在此，我们 假设无论KT后的最初伤害如何，炎症和氧化应激都会诱导表观遗传 关键基因的修饰，导致纤维化风险增加和肾功能进行性下降。 这些表观遗传修饰导致特定的细胞生物标记物分泌到循环和尿液中， 预测肾脏纤维化和慢性移植物功能障碍的风险。具体目标(SA)包括：SA1： 从人肾移植纵向队列中顺序确定KT后的表观遗传修饰 活组织检查。SA2：开发预测模型，通过整合来分层发生纤维化和功能丧失的风险 最具预测性的表观遗传学、转录组和临床标志物。SA3：评估循环小非编码 RNA(SNcRNA)谱识别生物标记物及其与移植肾基因表达变化的相关性 有纤维化和冠心病。评估移植肾的表观遗传学变化可能提供有关受影响的新数据 导致移植物损伤、纤维化和功能丧失的途径和调节因子。拟议的研究将提供 表观遗传修饰对分子通路和上游调控因子引导的影响的信息 致民航局。由此产生的非侵入性生物标志物将更好地预测和分层移植物损伤和纤维化进展， 有可能改善肾移植的长期结果。

Late graft loss continues to be a major problem after kidney transplantation (KT), mainly as consequence of death with a functioning graft and intrinsic allograft failure (or chronic allograft dysfunction (CAD)). CAD remains a major cause of allograft attrition over time, resulting in reinstitution of end-stage renal disease care. CAD is considered by many to be a variant of chronic kidney disease (CKD), with both immune and non-immune mechanisms, contributing to the development of interstitial fibrosis, tubular atrophy (IFTA) and progressive loss of graft function. Early development of graft fibrosis is predictive of late graft function. To study early factors involved in kidney fibrosis progression, we established a cohort of 298 KT patients followed longitudinally, with sequential genomic sampling of kidney allografts. Paired peripheral samples are also available. Utilizing this unique resource, we have made these observations: a) Molecular activators of early graft injury among KT recipients with kidney allografts progressing to fibrosis are independent of initial cause of injury, b) there is an constant pro-inflammatory and oxidative stress proclivity in the allografts from patients progressing to CRAD, c) specific DNA methylation (DNAm) patterns in donor kidney tissue associate with short- and long-term outcomes post-KT, d) there are major DNAm pattern changes between cross-sectional kidney allograft biopsies with IFTA and decline of graft function and kidney graft biopsies with normal histology and graft function (NFA) at > 2-years post-KT, and e) preliminary data demonstrate that specific upstream epigenetic modifications are associated with canonical gene pathways related to enhanced immune response and impaired allograft reparation. An independent Cohort 2 (multicenter, five Institutions) will be used for validation and replication. Hereby, we hypothesize that regardless of the initial insult after KT, inflammation and oxidative stress induce epigenetic modifications of critical genes, resulting in an increased risk of fibrosis and progressive decline of kidney function. These epigenetic modifications lead to secretion of specific cellular biomarkers into the circulation and urine that predict the risk of kidney fibrosis and chronic allograft dysfunction. The specific aims (SA) include: SA1: Determine post-KT epigenetic modifications sequentially from a longitudinal cohort of human renal allograft biopsies. SA2: Develop predictive models to stratify the risk of developing fibrosis and function loss by integrating the most predictive epigenetic, transcriptome, and clinical markers. SA3: Evaluate circulating small non-coding RNA (sncRNA) profiles to identify biomarkers and correlate with gene expression changes in the renal allograft with fibrosis and CAD. Evaluation of epigenetic changes in kidney grafts may provide new data about affected pathways and regulators leading to graft injury, fibrosis, and loss of function. The proposed studies will provide information about the effect of epigenetic modifications on molecular pathways and upstream regulators leading to CAD. Resulting non-invasive biomarkers will better predict and stratify graft injury and fibrosis progression, potentially improving long-term renal graft outcomes.