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 的发病率不断上升，需要新的策略来对抗这种令人衰弱的疾病。 DN 的主要特征包括由于细胞外基质 (ECM) 蛋白的积累导致肾小球硬化和系膜细胞扩张增加。尽管一些生化途径和关键的促纤维化因子，例如转化生长因子-b1 (TGFb1) 和 ECM 蛋白胶原，与 DN 的发病机制有关，但调节它们的微妙分子机制尚不清楚。在之前的资助期间，我们确定了肾脏 microRNA (miRNA) 在 DN 发病机制中的新作用。我们证明 miR-192 可以介导 TGF b1 诱导系膜细胞 (MC) 中的胶原蛋白表达，并且 miR-192 缺陷可以预防小鼠模型中 DN 的关键特征。从那时起，肾脏 miRNA 在各种肾脏疾病中受到越来越多的关注，并且也被认为是有前途的 DN 临床生物标志物。然而，我们对改变 DN 进展的 miRNA 谱及其治疗潜力的了解仍然有限。我们的目标是通过确定新发现的 miRNA 及其宿主基因在 DN 发病机制中的作用，以及利用转化方法来利用其潜力来满足对更好的 DN 治疗的关键需求，从而弥补这一知识空白。我们将跟进大量新的初步数据，这些数据表明，体外 MC 中以及体内糖尿病小鼠肾小球中，TGFb1 和高葡萄糖共同上调了一种新型 miRNA“巨型簇”。此外，我们发现这个簇嵌入在一个长转录本中，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 miRNA 巨簇的上调会抑制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，从而加速 DN 进展。这一假设将通过三个具体目标进行检验，这些目标将： i) 研究巨型簇内关键 miRNA 调控的分子机制； ii) 确定这些 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在 DN 小鼠模型中下调该 miRNA 簇基因组区域的翻译方法。这些概念上创新且具有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，从而确定急需的 DN 新治疗靶点，从而对该领域的发展产生积极影响。