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

剖析动态表观基因组促进途径导致肾同种异体移植纤维化的作用

• 批准号: 10228103
• 负责人: Valeria Raquel Mas
• 金额: $ 67.36万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228103
• 关键词: Affect; Allografting; Antisense Oligonucleotides; Atrophic; Biological Markers; Biopsy; Blood Circulation; Caring; Cessation of life; Chronic; Chronic Kidney Failure; Clinical; Clinical Data; Clinical Markers; Custom; DNA Methylation; Data; Development; Early Diagnosis; End stage renal failure; Epigenetic Process; Epithelial Cells; Evaluation; Failure; Fibrosis; Functional disorder; Gene Expression; Gene Expression Profiling; Genes; Genomics; Health Care Costs; Histology; Human; Immune; Immune response; Impairment; Inflammation; Inflammatory; Injury; Institution; Intervention; Kidney; Kidney Transplantation; Lead; Longitudinal cohort; Mediating; Messenger RNA; MicroRNAs; Modeling; Modification; Molecular; Monitor; Morbidity - disease rate; Outcome; Oxidative Stress; Pathway interactions; Patients; Pattern; Peripheral; Plasma; Prevalence; Prevention; Quality of life; Regulation; Renal function; Reperfusion Therapy; Resources; Risk; Role; Sampling; Testing; Time; Tissues; Training; Transplant Recipients; Tubular formation; Untranslated RNA; Urine; Validation; Variant; bioinformatics tool; biomarker discovery; cohort; epigenome; extracellular; fibrogenesis; graft function; improved; inhibitor/antagonist; interstitial; kidney allograft; kidney fibrosis; laser capture microdissection; loss of function; methylation pattern; microvesicles; mortality; predictive modeling; preimplantation; risk stratification; therapeutic target; tool; transcriptome; wound healing

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.

肾脏移植（KT）后，晚期移植物损失仍然是一个主要问题，主要是由于死亡的结果 具有功能性的移植物和固有的同种异移植衰竭（或慢性同种异体功能障碍（CAD））。 CAD仍然是一个 随着时间的推移，同种异体移植流失的主要原因，导致终结肾脏疾病护理的恢复原状。 CAD是 许多人认为是慢性肾脏疾病（CKD）的变体，具有免疫和非免疫性 机制，有助于间质纤维化的发展，管状萎缩（IFTA）和进行性损失 移植功能。移植纤维化的早期发展可预测晚期移植功能。研究早期因素 参与肾脏纤维化进展，我们建立了一组298名KT患者的队列，纵向跟踪， 肾脏同种异体移植的顺序基因组采样。还提供配对的外围样品。利用这个 独特的资源，我们进行了这些观察：a）KT早期移植物损伤的分子激活剂 肾脏同种异体移植到纤维化的接受者与最初的受伤原因无关，b）有一个 从发展到Crad的患者的同种异体移植物中持续的促炎和氧化应激倾向，C） 供体肾脏组织中的特定DNA甲基化（DNAM）模式与短期和长期结局有关 KT后，D）与IFTA的横截面肾脏同种异体移植活检之间存在重大的DNAN模式变化 在> 2年以上 KT后和E）初步数据表明，特定的上游表观遗传修饰是相关的 具有与增强的免疫反应和同种异体移植赔偿有关的规范基因途径。一个 独立队列2（多中心，五个机构）将用于验证和复制。特此，我们 假设无论KT之后的初始侮辱，炎症和氧化应激都会引起表观遗传 关键基因的修饰，导致纤维化的风险增加和肾功能的逐渐下降。 这些表观遗传修饰导致特定的细胞生物标志物分泌到循环和尿液中 预测肾脏纤维化和慢性同种异体功能障碍的风险。具体目的（SA）包括：SA1： 从人肾脏同种异体移植的纵向队列中顺序确定KT后表观遗传修饰 活检。 SA2：开发预测模型，以整合纤维化和功能损失的风险 最预测的表观遗传学，转录组和临床标记。 SA3：评估循环的小型非编码 RNA（SNCRNA）剖面以鉴定生物标志物并与肾脏同种异体移植中的基因表达变化相关 纤维化和CAD。评估肾脏移植物的表观遗传变化可能会提供有关受影响的新数据 途径和调节剂导致移植损伤，纤维化和功能丧失。拟议的研究将提供 有关表观遗传修饰对分子途径和上游调节剂的影响的信息 到CAD。导致的非侵入性生物标志物将更好地预测和分层移植损伤和纤维化进展， 有可能改善长期肾脏移植结果。