MicroRNA In Diabetic Nephropathy

糖尿病肾病中的 MicroRNA

• 批准号: 10381348
• 负责人: FARHAD R DANESH
• 金额: $ 46.03万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10381348
• 关键词: Address; Area; Binding Proteins; Biological; Biological Markers; Carbohydrates; Cardiovascular Pathology; Cell Nucleus; Characteristics; Clinical Research; Communication; Complement; Cytoplasm; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Diabetic mouse; Diagnostic; Disease; Experimental Models; Funding; Future; Gene Expression; Genes; Genetic Transcription; Glucose; Goals; Homeostasis; Investigation; Kidney; Label; Laboratories; Malignant Neoplasms; Mediating; Medical; Medicine; MicroRNAs; Mitochondria; Modeling; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nucleotides; Open Reading Frames; PPAR gamma; Pathogenesis; Pathologic; Pathology; Patients; Peptides; Process; Property; Proteins; Publishing; RNA; Regulation; Research; Response Elements; Role; Taurine; Techniques; Therapeutic; Tissues; Transcript; Transgenic Mice; Translating; Untranslated RNA; Work; db/db mouse; diabetic; expectation; genetic approach; in vivo; mitochondrial fitness; mitochondrial metabolism; mutant mouse model; neurological pathology; new therapeutic target; next generation; overexpression; podocyte; protective effect; response; targeted treatment; therapeutic target; transcription factor

PROJECT SUMMARY/ABSTRACT We are witnessing a paradigmatic shift in the practice of medicine whereby the concept of targeting RNAs as diagnostic and therapeutic strategies are rapidly evolving. Lon noncoding RNAs (lncRNAs) are a highly heterogeneous group of non-coding transcripts that participate in the regulation of almost every stage of gene expression, as well as being involved in a variety of disease states. Dysregulation of several lncRNAs have also been implicated in progression of diabetic nephropathy (DN) and because of the tissue-specific characteristics of lncRNAs, they are considered as the next generation of biomarkers and promising therapeutic targets for DN progression In the last funding cycle, our lab provided strong evidence that lncRNATug1 is down regulated in several experimental models of DN and in patients with Type 2 diabetes (Long, et al. JCI, 2016). Importantly, conditional overexpression of Tug1 in podocytes mitigated progression of DN. We also published our findings demonstrating that Tug1-mediated renoprotection in DN is accomplished through a PGC1a-dependent mechanisms on mitochondrial function. Thus, we proposed that Tug1 serves as a novel therapeutic target in DN progression. Our work over the last five years suggests that Tug1 has two major effects on mitochondrial function: 1) Tug1 impacts mitochondrial function indirectly through a PGC1a-dependent mechanism in the nucleus, and 2) we now provide preliminary data suggesting that Tug1 is also translocated from the nucleus to mitochondria. However, the impact of mitochondrial-associated Tug1 (mitoTug1) remains unknown. We also provide preliminary data that Tug1 transcripts localized to the cytoplasm is translated into micropeptides. Several lncRNAs have been shown to hide small open reading frames (sORFs) encoding for small functional peptides termed micropeptides. Our preliminary findings suggest a direct effect of Tug1 encoded micropeptide on mitochondrial function. However, its role on mitochondrial homeostasis and progression of DN is unknown. In this application, we propose a convergent model of Tug1-mediated impact on mitochondrial remodeling in DN. Two fundamental questions will be addressed: 1) First, elucidating the subcellular distribution and function of mitochondrial-associated Tug1 (mitoTug1) on mitochondrial homeostasis and progression of DN, and 2) Second, identifying the biological and pathological role of a Tug1-encoded micropepetide on mitochondrial function and DN progression. We will describe the various techniques and strategies to study the potential role of Tug1 on mitochondrial remodeling, the challenges to these approaches, and our published and preliminary data. The successful completion of our application will place high priority on developing strategies to target Tug1 as a potential candidate in future clinical studies, and open a rich field for investigation on the interorganelle communication and mitochondrial metabolism in the pathogenesis of DN.

项目总结/摘要 我们正在见证医学实践的范式转变，靶向RNA的概念 因为诊断和治疗策略正在迅速发展。Lon非编码RNA（lncRNA）是一种高度表达的 非编码转录物的异质组，参与基因的几乎每个阶段的调节 表达，以及参与各种疾病状态。几种lncRNA的失调 也与糖尿病肾病（DN）的进展有关， 由于lncRNA具有独特的生物学特性，它们被认为是下一代生物标志物， DN进展的治疗靶点 在上一个融资周期中，我们的实验室提供了强有力的证据，表明lncRNATug 1在几个 DN实验模型和2型糖尿病患者（Long等人，JCI，2016）。重要的是， 足细胞中Tug 1的条件性过表达减轻了DN的进展。我们还发表了我们的发现 这表明Tug 1介导的DN肾保护作用是通过PGC 1a依赖的 线粒体功能的机制。因此，我们提出Tug 1作为一个新的治疗靶点， DN进展。 我们在过去五年的研究表明，Tug 1对线粒体功能有两个主要影响：1） Tug 1通过细胞核中的PGC 1a依赖机制间接影响线粒体功能，以及2） 我们现在提供的初步数据表明，Tug 1也从细胞核转移到线粒体。 然而，与线粒体相关的Tug 1（mitoTug 1）的影响仍然未知。我们还提供 初步数据表明，Tug 1转录本定位于细胞质被翻译成微肽。几 已显示lncRNA隐藏编码小功能肽的小开放阅读框（sORF 称为微肽。我们的初步研究结果表明，Tug 1编码的微肽对 线粒体功能然而，其在线粒体稳态和DN进展中的作用尚不清楚。 在这个应用中，我们提出了一个收敛模型Tug 1介导的影响线粒体重塑 在DN。两个基本问题将得到解决：1）首先，阐明亚细胞分布， 线粒体相关Tug 1（mitoTug 1）在线粒体稳态和DN进展中的作用， 和2）第二，鉴定Tug 1编码的微肽在肿瘤细胞中的生物学和病理学作用。 线粒体功能和DN进展。我们将描述各种技术和策略来研究 Tug 1对线粒体重塑的潜在作用，这些方法的挑战，以及我们发表的和 初步数据。成功完成我们的应用程序将高度重视发展战略 将Tug 1作为未来临床研究的潜在候选靶点，并为研究Tug 1的作用开辟了丰富的领域。 细胞器间通讯和线粒体代谢在DN发病中的作用。