Transforming growth factor beta1, microRNAs and diabetic nephropathy

转化生长因子β1、microRNA 和糖尿病肾病

基本信息

批准号：
8772669
负责人：
RAMA NATARAJAN
金额：
$ 43.06万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8772669
关键词：
Address Attention Biochemical Pathway Biological Markers Cellular Stress Clinical Collagen Complications of Diabetes Mellitus Data Development Diabetes Mellitus Diabetic Nephropathy Diabetic mouse Dialysis procedure Disease End stage renal failure Extracellular Matrix Extracellular Matrix Proteins Fibrosis Functional RNA Functional disorder Funding Gene Targeting Genes Genetic Genomics Glomerular Mesangial Cell Glucose Goals Growth Factor Guide RNA Healthcare Hypertrophy In Vitro Injury Investigation Kidney Kidney Diseases Kidney Failure Knockout Mice Knowledge Lead Mediating Messenger RNA Methods MicroRNAs Molecular Morbidity - disease rate National Institute of Diabetes and Digestive and Kidney Diseases Pain Paper Pathogenesis Phenotype Protein Biosynthesis Proteins Publishing Regulation Reporting Role Small Interfering RNA Stress Technology Testing Therapeutic Transcript Transcription Process Transcriptional Regulation Transforming Growth Factors Translations Up-Regulation Validation biological adaptation to stress clinically relevant clinically significant combat diabetic endoplasmic reticulum stress follow-up genome-wide glomerulosclerosis human TGFB1 protein in vivo inhibitor/antagonist innovation loss of function meetings mesangial cell mortality mouse model new therapeutic target novel nuclease public health relevance response transcription factor transcription factor CHOP translational approach type I and type II diabetes

项目摘要

DESCRIPTION (provided by applicant): Diabetic nephropathy (DN) is one of the major complications of diabetes that can lead to end stage renal disease. The rates of DN are escalating and new strategies are needed to combat this debilitating condition. Key features of DN include increased glomerulosclerosis and mesangial cell expansion due to the accumulation of extracellular matrix (ECM) proteins. Although several biochemical pathways and key profibrotic factors, such as transforming growth factor-b1 (TGFb1) and the ECM protein collagen, have been implicated in the pathogenesis of DN, the subtle molecular mechanisms regulating them are unclear. In the previous funding period we identified new roles for renal microRNAs (miRNAs) in the pathogenesis of DN. We demonstrated that miR-192 can mediate TGF b1 induced collagen expression in mesangial cells (MCs), and that miR-192 deficiency can protect against key features of DN in mouse models. Since then, renal miRNAs have gained increased attention in various renal diseases, and are also being recognized as promising clinical biomarkers for DN. However, we still have only limited knowledge about the spectrum of miRNAs that modify DN progression and their therapeutic potential. Our objective is to address this gap in knowledge by identifying the roles of newly identified miRNAs and their host genes in the pathogenesis of DN, and translational approaches to harness their potential to meet the critical need for better therapies for DN. We will follow up on extensive new preliminary data showing that a novel "Mega Cluster" of miRNAs is collectively up-regulated by TGFb1 and high glucose in vitro in MCs, and in diabetic mice glomeruli in vivo. Furthermore, we find that this cluster is embedded within a long transcript and both are regulated by stress responsive transcription factors, whereas target genes of multiple component miRNAs regulate protein translation, hypertrophy and cellular stress. The central hypothesis is that up-regulation of the mega cluster of miRNAs diabetic conditions suppresses the expression of their key functional gene targets, inducing glomerular MC hypertrophy, protein synthesis and fibrosis, and thereby augmenting DN progression. This hypothesis will be tested via three Specific Aims which will: i) examine the molecular mechanisms of regulation of key miRNAs within the mega cluster; ii) identify the functional roles of these miRNAs and key common target genes in MCs, and iii) finally evaluate novel gene targeting as well as translational approaches to down-regulate this miRNA cluster genomic region in mouse models of DN. The results of these conceptually innovative and clinically significant studies can define currently unknown regulatory factors in the diabetic kidney that could lead to the identification of critically needed new therapeutic targets for DN and thus have a positive impact to advance the field.

描述（由申请人提供）：糖尿病性肾病（DN）是糖尿病的主要并发症之一，可导致终结阶段肾脏疾病。 DN的速度正在升级，需要新的策略来应对这种令人衰弱的状况。 DN的关键特征包括由于细胞外基质（ECM）蛋白的积累而增加的肾小球硬化和肾小球细胞扩张。尽管几种生化途径和关键纤维化因子（例如转化生长因子-B1（TGFB1）和ECM蛋白胶原蛋白）与DN的发病机理有关，但调节它们的微妙分子机制尚不清楚。在上一个资金期间，我们确定了肾脏microRNA（miRNA）在DN发病机理中的新作用。我们证明了miR-192可以介导TGF B1诱导的膜根细胞（MCS）胶原蛋白表达，并且miR-192缺乏可以保护小鼠模型中DN的关键特征。从那时起，肾脏miRNA在各种肾脏疾病中引起了人们的注意，也被认为是DN的有希望的临床生物标志物。但是，我们仍然只有关于修改DN进展及其治疗潜力的miRNA谱的知识有限。我们的目标是通过确定新鉴定的miRNA及其宿主基因在DN发病机理中的作用以及利用其潜力满足对DN疗法的关键需求的潜力来解决知识的差距。我们将跟进广泛的新初步数据，表明MIRNA的新型“ Mega Cluster”在MC中被TGFB1和高葡萄糖集体上调，在Vivo中，MCS和糖尿病小鼠肾小球中的高葡萄糖。此外，我们发现该簇嵌入了长的转录本中，两者都受到应力响应转录因子的调节，而多组分miRNA的靶基因调节蛋白质翻译，肥大和细胞应激。中心假设是，miRNA糖尿病疾病的大型大型簇簇抑制其关键功能基因靶标的表达，从而诱导肾小球MC肥大，蛋白质合成和纤维化，从而增强DN进展。该假设将通过三个特定目的进行检验：i）检查巨型簇中关键miRNA调节的分子机制； ii）在MC中确定这些miRNA和关键共同靶基因的功能作用，iii）最终评估了新型基因靶向以及在DN小鼠模型中下调该miRNA簇基因组区域的转化方法。这些概念上创新和临床意义的研究的结果可以定义糖尿病肾脏中当前未知的调节因素，这可能导致鉴定DN的急需新的治疗靶标，从而对推进该领域产生积极影响。