miRNA Mediated Cross-Talk in CRS4: The Role of the miR-21-5p/PPAR-Alpha Pathway

miRNA 介导的 CRS4 交叉对话：miR-21-5p/PPAR-Alpha 通路的作用

• 批准号: 9918443
• 负责人: Alison J Kriegel
• 金额: $ 38.5万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918443
• 关键词: Adult; Agonist; Animal Model; Atherosclerosis; Basic Science; Biological; Blood Circulation; Blood Pressure; Cardiac; Cardiac development; Cardiomegaly; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Death; Cell Proliferation; Cells; Chronic Kidney Failure; Clinical Data; Clofibrate; Data; Development; Disease; Disease Marker; Disease Progression; Documentation; Exhibits; Functional disorder; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Genes; Genomics; Glycolysis; Goals; Heart; Heart Diseases; Heart Hypertrophy; Human; In Vitro; Inflammation; Kidney; Kidney Diseases; Kidney Transplantation; Knock-out; Left Ventricular Remodeling; Left ventricular structure; Measurement; Measures; Mediating; Mediator of activation protein; MicroRNAs; Modeling; Molecular; Myocardial Infarction; Myocardial dysfunction; Nephrectomy; Organ; PPAR alpha; Pathologic; Pathology; Pathway interactions; Patients; Plasma; Post-Transcriptional Regulation; Process; Protocols documentation; Rattus; Regulation; Renal function; Reporting; Research; Risk; Risk Factors; Role; Signal Transduction; Signaling Protein; Small RNA; Source; Sprague-Dawley Rats; Syndrome; Therapeutic; Tissues; Transcript; Transplantation; United States; Up-Regulation; Work; blood pressure reduction; cardioprotection; cardiovascular disorder risk; cell type; circulating microRNA; design; effective therapy; fatty acid oxidation; heart damage; heart function; immune function; improved; in vivo; innovation; knock-down; mRNA sequencing; novel therapeutic intervention; pressure; prevent; response; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT: Chronic kidney disease (CKD) puts patients at a greatly increased risk of cardiovascular disease, in a condition termed Type 4 Cardiorenal Syndrome (CRS4). While a large amount of clinical data on CKD patients has identified some risk factors, very little is known about the mechanisms by which this condition develops. We have utilized the 5/6 nephrectomy (5/6 NX) model in Sprague Dawley rats to study the development of cardiac dysfunction resulting from declining kidney function in a controlled animal model. The goal of our work is to identifying molecular mechanisms that are mediating dysfunction and target them therapeutically. Small RNA sequencing of left ventricle tissue identified miR-21-5p as a microRNA that is upregulated in response to 5/6 NX. MicroRNAs are a class of several hundred endogenously produced small RNAs that are involved with post-transcriptional regulation of gene expression in the heart and elsewhere. Systemic knockdown of miR-21 prevented cardiac hypertrophy and enhanced cardiac function without improving renal function or reducing blood pressure. This data suggests that suppression of miR-21-5p prevented pathology through pressure independent mechanisms. Subsequent mRNA sequencing identified gene expression changes in pathways relating to fatty acid oxidation, glycolysis, hypertrophic signaling, inflammation, immune function and atherosclerosis in response to miR-21 knockdown, suggesting that miR-21-5p may be targeting peroxisome proliferator-activated receptor alpha (PPAR. PPAR is miR-21 target in humans and is involved with regulation of all of the above mentioned pathways. PPAR is well known to be suppressed with cardiac pathology, however miR-21 targeting of PPARa has not yet been reported in a model of cardiac disease. We hypothesize that miR-21-5p produced by the 5/6Nx remnant kidney supplies the LV with a pathological amount of miR-21-5p, contributing to cardiac remodeling and dysfunction, at least in part, through targeting PPAR. This proposal will focus understanding the functional and pathological implications of that regulation. We will also locate LV cell types and tissue regions in which miR-21 targeting of PPAR is occurs and study the gene expression changes that result. A role for the miR-21-5p/PPAR pathway has not been reported in CRS4, or any other cardiac pathology. The studies outlined in this proposal are designed to characterize the upstream and downstream mechanisms of this pathway in the 5/6Nx model. The discovery of a direct role for circulating miR-21-5p in disease development would be an innovative breakthrough in the field of microRNA research, expanding our understanding of circulating miRNAs from markers of disease to mediators of disease. Further, findings from the proposed study could help elucidate mechanisms that regulate cardiac dysfunction in CRS4 and identify new therapeutic approaches for preventing or improving cardiac dysfunction in CKD patients.

项目总结/摘要： 慢性肾病（CKD）使患者的心血管疾病风险大大增加。 疾病，在称为4型肾综合征（CRS4）的条件。虽然大量的 CKD患者的临床数据已经确定了一些风险因素，但对CKD患者的风险因素知之甚少。 这种情况发展的机制。我们采用5/6肾切除术（5/6NX） 在Sprague道利大鼠中建立模型，以研究 在对照动物模型中肾功能下降。我们工作的目标是 介导功能障碍的分子机制，并将其作为治疗目标。小 左心室组织的RNA测序将miR-21 - 5 p鉴定为上调的微小RNA 5/6 NX的响应。microRNA是一类由数百种内源性产生的 参与心脏基因表达转录后调控的小RNA 和其他地方。miR-21的系统性敲低可防止心肌肥大，并增强心肌细胞的增殖。 心功能不改善肾功能或降低血压。该数据 提示miR-21 - 5p的抑制通过压力非依赖性途径预防病理学， 机制等随后的mRNA测序确定了通路中的基因表达变化， 与脂肪酸氧化、糖酵解、肥大信号、炎症、免疫功能有关 和动脉粥样硬化，这表明miR-21 - 5p可能是 靶向过氧化物酶体增殖物激活受体α（PPAR α）。PPAR γ是miR-21的靶点， 人，并参与所有上述途径的调节。PPAR γ是良好的 已知在心脏病理学中受到抑制，然而，miR-21靶向PPARa并没有 在心脏病模型中也有报道。我们假设，miR-21 - 5p的产生是由 5/6Nx残肾为LV提供病理量的miR-21 - 5p， 心脏重塑和功能障碍，至少部分是通过靶向PPAR γ。这项建议 将重点了解该调节的功能和病理意义。我们将 还定位发生miR-21靶向PPAR γ的LV细胞类型和组织区域， 研究基因表达的变化。miR-21 - 5p/PPAR γ通路的作用是 未在CRS 4或任何其他心脏病理学中报告。本提案中概述的研究 旨在表征这一途径的上游和下游机制， 5/6Nx型号。发现循环miR-21 - 5p在疾病发展中的直接作用 这将是microRNA研究领域的一个创新突破， 从疾病标志物到疾病介质的循环miRNAs的理解。此外，本发明还 这项研究的结果有助于阐明调节心脏功能的机制， CRS4功能障碍，并确定新的治疗方法，以预防或改善 CKD患者的心功能不全。