Role of mitochondrial microRNAs (mitomiRs) in endogenous renal repair

线粒体 microRNA (mitomiRs) 在内源性肾修复中的作用

基本信息

批准号：
10583380
负责人：
Alfonso Eirin
金额：
$ 47.2万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10583380
关键词：
3-Dimensional Address Attenuated Bioenergetics Biogenesis Cell Nucleus Cell physiology Cells Characteristics Cytosine Cytosol DNA Data Deterioration Development Dioxygenases Down-Regulation Elderly End stage renal failure Enhancers Enzymes Epigenetic Process Epithelial Cells Event Exhibits Family suidae Fibrosis Functional Imaging Functional disorder Gene Expression Gene Silencing Gene Targeting Genes Genetic Transcription Harvest Histones Homeostasis Hypertension Imaging Techniques Impairment In Vitro Inflammation Infusion procedures Injury to Kidney Kidney Kidney Diseases Measures Methylation MicroRNAs Mitochondria Mitochondrial DNA Morbidity - disease rate Nuclear Oxidation-Reduction Phenotype Pilot Projects Polyribonucleotide Nucleotidyltransferase Population Process Production Proliferating Protein Import Regulator Genes Renal Artery Stenosis Renal function Role Structural defect Structure System Techniques Testing Tubular formation alpha ketoglutarate cell injury clinically relevant cofactor experimental study genome-wide improved in vivo inhibitor injured insight kidney repair miRNA expression profiling migration mortality novel novel strategies oxidation paracrine porcine model posttranscriptional preservation progenitor promoter protective effect renal ischemia repaired reparative capacity tool

项目摘要

Renal artery stenosis (RAS) remains a common cause of hypertension and end-stage renal disease in the elderly population, associated with increased morbidity and mortality. Recent data suggest that renal ischemia in RAS interferes with endogenous kidney repair mechanisms, such as CD133+/CD24+ scattered tubular-like cells (STCs), which can proliferate and their progeny re-differentiate into tubular epithelial cells to replace lost neighboring injured tubular cells. Our previous studies have shown that experimental RAS impairs the reparative capacity of swine STCs by inducing structural and functional abnormalities in their mitochondria. However, the processes underpinning RAS-induced STC mitochondrial damage remain unclear. Micro-RNAs (miRNAs) function as post-transcriptional regulators of gene expression. MiRNA genes are transcribed in the nucleus, which results in the production of pri- and pre-miRNA precursors, and subsequently mature miRNAs. Although most mature miRNAs are present in the cytosol, few miRNAs, known as ‘mitomiRs’, translocate to the mitochondrion to silence gene expression related to mitochondrial functions. Our preliminary data show that RAS increases expression of the mitomiR-181c in swine STCs associated with decreased expression of its mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) encoded mitochondrial gene targets, and in turn mitochondrial structural abnormalities and dysfunction. In addition, we found that the promoters and enhancers of the miR-181c gene (MIR181C) exhibit hyper 5-hydroxymethylation of cytosine (5hmC), an epigenetic mark generated by the oxidation of 5mC by the ten-eleven translocation methylcytosine dioxygenase (TET) enzyme. Excitingly, in our pilot studies anti-miR-181c, the TET inhibitor Bobcat339, and inhibitors of the mitomiR import proteins ameliorate mitochondrial damage in swine-STCs. Our central hypothesis is thus that altered miR-181c expression in STCs underlies RAS-induced STC mitochondrial damage, blunting the paracrine function and capacity of STCs to preserve the post- stenotic kidney. Three specific aims will be pursued: Aim 1: will test whether increased miR-181c expression in RAS-STCs induces mitochondrial structural damage and dysfunction in STCs. Aim 2: will test whether RAS imposes epigenetic changes that increase miR-181c expression in STCs. Aim 3: will test whether aberrant miR-181c mitochondrial import contributes to STC dysfunction. Successful studies will provide novel insight into the vulnerability of this repair system and may contribute towards development of feasible clinically relevant tools for improving the utility and efficacy of kidney repair in renal disease.

肾动脉狭窄（RAS）仍然是高血压和终末期肾病的常见原因老年人口，与发病率和死亡率增加有关。最近的数据表明，肾缺血。 RAS中干扰内源性肾脏修复机制，如CD133+/CD24+分散的管状细胞（STC），可以增殖并且其后代重新分化为肾小管上皮细胞以替代丢失的肾小管上皮细胞我们之前的研究表明，实验性 RAS 会损害邻近受损的肾小管细胞。通过诱导线粒体结构和功能异常来增强猪 STC 的修复能力。然而，RAS 诱导的 STC 线粒体损伤的过程仍不清楚。 Micro-RNA (miRNA) 充当基因表达的转录后调节因子。在细胞核中转录，导致 pri- 和 pre-miRNA 前体的产生，随后尽管大多数成熟的 miRNA 存在于细胞质中，但很少有 miRNA（称为“mitomiR”），易位至线粒体以沉默与线粒体功能相关的基因表达。我们的初步数据表明 RAS 增加了猪 STC 中 mitomiR-181c 的表达线粒体 DNA (mtDNA) 和编码线粒体的核 DNA (nDNA) 表达减少此外，我们发现线粒体结构异常和功能障碍。 miR-181c 基因 (MIR181C) 的启动子和增强子表现出胞嘧啶的超 5-羟甲基化 (5hmC)，由 10-11 易位甲基胞嘧啶氧化 5mC 产生的表观遗传标记令人兴奋的是，在我们的初步研究中，抗 miR-181c、TET 抑制剂 Bobcat339 和 mitomiR 输入蛋白的抑制剂可改善猪 STC 中的线粒体损伤。因此，我们的中心假设是，STC 中 miR-181c 表达的改变是 RAS 诱导的 STC 的基础线粒体损伤，削弱 STC 的旁分泌功能和保存后细胞的能力将追求三个具体目标：目标 1：将测试 miR-181c 表达是否增加。 RAS-STC 中的线粒体结构损伤和 STC 功能障碍目标 2：将测试 RAS 是否存在。目标3：测试是否异常 miR-181c 线粒体输入导致 STC 功能障碍。成功的研究将提供新的见解。研究该修复系统的脆弱性，并可能有助于开发可行的临床提高肾脏修复在肾脏疾病中的实用性和功效的相关工具。