MicroRNA In Diabetic Nephropathy

糖尿病肾病中的 MicroRNA

基本信息

批准号：
8730138
负责人：
FARHAD R DANESH
金额：
$ 34.8万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
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/8730138
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

项目摘要

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.

描述（由申请人提供）：该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 microRNA（miRNA）及其靶基因。 MicroRNA 构成一类高度保守的非编码 RNA，通过抑制 mRNA 的翻译或破坏其稳定性，充当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，例如 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 的发病机制。我们的假设基于几个新的观察结果：1) 我们最近基于比较 microRNA 阵列表明 miR-93 是糖尿病环境中的“标志性”miRNA，2) 我们首次证明 miR-93 在糖尿病环境中发挥着重要作用。在体外和体内高血糖条件下调节 VEGF-A 表达的关键作用 (Long J. et al. J. Biol. Chem. 2010)，以及 3) miR-93 的靶向导致 VEGF 表达诱导型小鼠模型中 VEGF 分泌显着增加。基于这些初步观察，我们现在提出了一种集成的体外和体内方法来测试三个特定目标。目标 1：评估 miR-93 在 DN 小鼠模型中条件性组织特异性强制表达的效果，目标 2：定义 miR-93 在体外和体内发挥作用的分子靶标。目标 3：足细胞中小鼠 miR-93 启动子的葡萄糖响应元件 (GRE) 的表征。该申请的研究结果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，我们的研究不仅将揭示 miR-93 在高血糖条件下的作用，还将揭示 VEGF 在糖尿病肾病中的病理学。第三，我们将生成一个遗传模型来确认 miR-93 直接参与 DN 的发病机制。该遗传模型将提供有关 miR-93 的作用及其在 DN 中的潜在靶标的更多信息。