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

基本信息

批准号：
9278288
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
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9278288
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 Control Animal 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 Messenger RNA 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 cardiovascular disorder risk cell type circulating microRNA design disorder risk effective therapy fatty acid oxidation heart function immune function improved in vivo innovation knock-down novel therapeutic intervention pressure prevent response transcriptome sequencing

项目摘要

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.

项目概要/摘要：慢性肾脏病（CKD）使患者患心血管疾病的风险大大增加疾病，称为 4 型心肾综合征 (CRS4)。 CKD 患者的临床数据已经确定了一些危险因素，但人们对其知之甚少我们采用了 5/6 肾切除术 (5/6 NX)。斯普拉格道利大鼠模型研究心脏功能障碍的发展我们工作的目标是确定受控动物模型中肾功能下降的情况。介导功能障碍和小靶向治疗的分子机制。左心室组织的 RNA 测序发现 miR-21-5p 是一种上调的 microRNA 响应 5/6 NX 的 MicroRNA 是一类数百个内源产生的。参与心脏基因表达转录后调控的小RNA miR-21 的系统性敲除可防止心脏肥大并增强心脏肥大。心脏功能，但不改善肾功能或降低血压。表明抑制 miR-21-5p 通过压力独立来预防病理学随后的 mRNA 测序确定了基因表达途径的变化。与脂肪酸氧化、糖酵解、肥大信号、炎症、免疫功能相关和动脉粥样硬化对 miR-21 敲低的反应，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。PPAR 是 miR-21 的靶标人类并参与所有上述途径的调节。已知会因心脏病理学而受到抑制，但 miR-21 靶向 PPARa 并没有我们在心脏病模型中发现了 miR-21-5p。 5/6Nx 残余肾向左室提供病理量的 miR-21-5p，有助于该提案至少部分通过针对 PPARα 来改善心脏重塑和功能障碍。将重点了解该法规的功能和病理影响。还定位了发生 miR-21 靶向 PPARα 的 LV 细胞类型和组织区域，研究 miR-21-5p/PPARα 通路所产生的基因表达变化。尚未在 CRS4 或本提案中概述的任何其他心脏病学研究中报告。旨在表征该途径的上游和下游机制 5/6Nx 模型。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，扩大我们的研究范围对循环 miRNA 从疾病标记物到疾病介质的理解。拟议研究的结果可能有助于阐明调节心脏的机制 CRS4 功能障碍并确定预防或改善的新治疗方法 CKD 患者心功能不全。