Transforming growth factor beta1, microRNAs and diabetic nephropathy

转化生长因子β1、microRNA 和糖尿病肾病

• 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
• 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

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）：糖尿病肾病（DN）是糖尿病的主要并发症之一，可导致终末期肾病。DN的发病率正在上升，需要新的策略来对抗这种使人衰弱的疾病。DN的主要特征包括由于细胞外基质（ECM）蛋白积聚而导致的肾小球硬化和系膜细胞扩张增加。虽然一些生化途径和关键的促纤维化因子，如转化生长因子-b1（TGF-β 1）和ECM蛋白胶原蛋白，已被牵连在DN的发病机制，微妙的分子机制，调节他们还不清楚。在上一个资助期，我们确定了肾脏microRNAs（miRNAs）在DN发病机制中的新作用。我们证明了miR-192可以介导TGF β 1诱导的系膜细胞（MC）胶原蛋白表达，并且miR-192缺陷可以在小鼠模型中保护DN的关键特征。从那时起，肾脏miRNAs在各种肾脏疾病中得到了越来越多的关注，并且也被认为是DN的有前途的临床生物标志物。然而，我们仍然只有有限的知识谱的miRNAs，修改DN的进展和他们的治疗潜力。我们的目标是通过确定新发现的miRNAs及其宿主基因在DN发病机制中的作用，以及利用其潜力满足DN更好治疗的关键需求的翻译方法来解决这一知识缺口。我们将跟踪大量新的初步数据，这些数据表明，一种新的miRNA“Mega Cluster”在体外MC和体内糖尿病小鼠肾小球中被TGF β 1和高糖共同上调。此外，我们发现该簇嵌入在一个长的转录本中，并且两者都受到应激反应转录因子的调节，而多组分miRNA的靶基因调节蛋白质翻译、肥大和细胞应激。核心假设是，糖尿病条件下的大簇miRNAs的上调抑制了其关键功能基因靶标的表达，诱导肾小球MC肥大、蛋白质合成和纤维化，从而增强DN进展。这一假设将通过三个特定目的进行检验，这三个特定目的将：i）检查大簇内关键miRNA调控的分子机制; ii）鉴定这些miRNA和MC中关键共同靶基因的功能作用，以及iii）最终评估新的基因靶向以及翻译方法，以下调DN小鼠模型中该miRNA簇基因组区域。这些概念上创新和临床意义的研究结果可以定义糖尿病肾脏中目前未知的调节因素，这些因素可能导致确定DN急需的新治疗靶点，从而对推进该领域产生积极影响。