MicroRNA In Diabetic Nephropathy

糖尿病肾病中的 MicroRNA

• 批准号: 8236389
• 负责人: FARHAD R DANESH
• 金额: $ 34.04万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8236389
• 关键词: Address; Affinity; Albuminuria; Animal Model; Animals; Apoptosis; Biological; Cell physiology; Complex; Data; Diabetic Nephropathy; Disease; Down-Regulation; Elements; End stage renal failure; Environment; Functional RNA; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Models; Genetic Translation; Glucose; Heart Diseases; Hematopoiesis; Histology; Hyperglycemia; In Vitro; Individual; Injury; Innovative Therapy; Kidney; Kidney Diseases; Laboratories; Light; MCM7 gene; Malignant Neoplasms; Mediating; Messenger RNA; MicroRNAs; Modeling; Molecular Target; Mus; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Proteins; Regulation; Regulator Genes; Research; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic Uses; Time; Tissues; Untranslated RNA; Vascular Endothelial Growth Factors; angiogenesis; base; comparative; diabetic; disease phenotype; fight against; improved; in vivo; mouse model; novel; novel therapeutic intervention; novel therapeutics; overexpression; podocyte; prevent; promoter; protein function; stem; transcription factor

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to identify renal microRNAs (miRNAs) and their target genes that could potentially contribute to the progression of diabetic nephropathy (DN). MicroRNAs constitute a class of highly conserved noncoding RNAs that act as negative regulators of gene expression by either inhibiting the translation of mRNAs or destabilizing them. Because individual often regulate the expression of multiple target genes with related functions, dysregulation of a single microRNA can, in principle, microRNAs influence an entire gene network and thereby contribute to complex disease phenotypes such as DN. The main aim of the current proposed study is to evaluate the pathogenic role of microRNA-93 (miR-93) in DN. Our main hypothesis is that miR-93 contributes to the pathogenesis of DN via its modulatory involvement on VEGF signaling pathway. Our hypothesis is based on several novel observations: 1) we have recently shown miR-93 is a "signature" miRNA in the diabetic milieu based on comparative microRNA arrays, 2), we have shown for the first time that miR-93 plays a critical role in regulating VEGF-A expression in hyperglycemic conditions in vitro and in vivo (Long J. et al. J. Biol. Chem. 2010), and 3) targeting of miR-93 leads to a significant increase in VEGF secretion in an inducible mouse model of VEGF expression. Based upon these initial observations, we now propose an integrated in vitro and in vivo approach to test three specific aims. Aim 1: Assess the effect of conditional tissue-specific forced expression of miR-93 in the murine models of DN, Aim 2: Define the molecular targets through which miR-93 exerts its effect in vitro and in vivo. Aim 3: Characterization of glucose-responsive elements (GRE) of the mouse miR-93 promoter in podocytes. The findings of this application will provide a significant advance in three aspects: first, this proposal represents a new therapeutic approach, and potentially a new class of agents in the fight against diabetic kidney disease. Second, our research will shed light not only on the role of miR-93 in hyperglycemic conditions, but also on the pathobiology of VEGF in diabetic nephropathy. And third, we will generate a genetic model to confirm that miR-93 is directly involved in the pathogenesis of DN. This genetic model will provide additional information on the role of miR- 93, and its potential targets in DN. PUBLIC HEALTH RELEVANCE: Diabetic nephropathy represents the primary cause of ESRD in the US, underscoring the need for innovative therapies for preventing its progression. New evidence suggests that microRNAs in the kidney are key pathogenic factors in diabetic nephropathy. We propose that targeting of miR-93, a novel microRNA in the kidney, holds promise as a novel therapeutic strategy to ameliorate progression of diabetic nephropathy.

描述（由申请人提供）：本提案的长期目标是鉴定可能导致糖尿病肾病（DN）进展的肾脏微小RNA（miRNAs）及其靶基因。MicroRNA是一类高度保守的非编码RNA，通过抑制mRNA的翻译或使其不稳定来作为基因表达的负调节因子。由于个体经常调节具有相关功能的多个靶基因的表达，因此原则上，单个microRNA的失调可以影响整个基因网络，从而导致复杂的疾病表型，如DN。目前提出的研究的主要目的是评估microRNA-93（miR-93）在DN中的致病作用。我们的主要假设是miR-93通过调节VEGF信号通路参与DN的发病。我们的假设是基于几个新的观察：1）我们最近基于比较microRNA阵列显示miR-93是糖尿病环境中的“签名”miRNA，2）我们首次显示miR-93在体外和体内高血糖条件下调节VEGF-A表达中起关键作用（Long J.et al.J.Biol.Chem.2010），和3）miR-93的靶向导致VEGF表达的诱导型小鼠模型中VEGF分泌的显著增加。基于这些初步观察，我们现在提出了一个综合的体外和体内方法来测试三个特定的目标。目标1：评估miR-93的条件性组织特异性强制表达在DN小鼠模型中的作用，目的2：确定miR-93在体外和体内发挥其作用的分子靶标。目的3：小鼠足细胞中miR-93启动子的葡萄糖响应元件（GRE）的表征。该应用的发现将在三个方面提供重大进展：首先，该提案代表了一种新的治疗方法，并且可能是对抗糖尿病肾病的一类新药物。其次，我们的研究不仅将阐明miR-93在高血糖条件下的作用，还将阐明VEGF在糖尿病肾病中的病理生物学。第三，我们将建立一个遗传模型来证实miR-93直接参与DN的发病机制。该遗传模型将提供关于miR- 93的作用及其在DN中的潜在靶点的额外信息。 公共卫生相关性：糖尿病肾病是美国ESRD的主要原因，强调需要创新疗法来预防其进展。新的证据表明，肾脏中的microRNA是糖尿病肾病的关键致病因素。我们提出，靶向肾脏中的一种新的microRNA-miR-93，有望成为改善糖尿病肾病进展的一种新的治疗策略。