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.

项目摘要/摘要 我们正在见证医学实践的范式转变，在这种转变中，靶向RNA的概念 因为诊断和治疗策略正在迅速演变。Lon非编码RNAs(LncRNAs)是一种高度的 一组异质的非编码转录本，几乎参与基因的每个阶段的调控 表达，以及参与各种疾病状态。几个lncRNA的调节失调 也与糖尿病肾病(DN)的进展有关，因为组织特异性 LncRNAs的特点，被认为是下一代生物标志物，具有广阔的应用前景 糖尿病肾病进展的治疗靶点 在上一个资金周期中，我们的实验室提供了强有力的证据，表明lncRNatug1在几个方面下调了 糖尿病肾病和2型糖尿病患者的实验模型(Long，et al.JCI，2016)。重要的是 足细胞条件过表达Tug1可缓解糖尿病肾病的进展。我们还发表了我们的发现 Tug1介导的糖尿病肾病肾保护作用是通过依赖PGC1a实现的 线粒体功能的机制。因此，我们提出Tug1作为一种新的治疗靶点。 糖尿病肾病进展。 我们过去五年的工作表明，Tug1对线粒体功能有两个主要影响：1) Tug1通过在细胞核中依赖于PGC1a的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，Tug1也从细胞核转移到线粒体。 然而，线粒体相关Tug1(MitoTug1)的影响仍不清楚。我们还提供 初步数据表明，Tug1转录本定位于细胞质，被翻译成微肽。几个 已有研究表明，lncRNAs隐藏了编码小功能肽的小开放阅读框架(SORF) 称为微肽。我们的初步研究结果表明，Tug1编码的微肽直接作用于 线粒体功能。然而，它在线粒体动态平衡和糖尿病肾病进展中的作用尚不清楚。 在这个应用中，我们提出了一个Tug1介导的影响线粒体重塑的收敛模型 在目录号码中。将解决两个基本问题：1)首先，阐明亚细胞的分布和 线粒体相关Tug1(MitoTug1)在线粒体内稳态和糖尿病肾病进展中的作用 2)第二，鉴定Tug1编码的微肽在生物学和病理学上的作用 线粒体功能与糖尿病肾病进展。我们将描述各种技术和策略来研究 Tug1在线粒体重塑中的潜在作用，这些途径面临的挑战，以及我们发表的和 初步数据。成功完成我们的申请将高度重视发展战略 将Tug1作为未来临床研究的潜在候选者，为研究Tug1开辟了丰富的领域 细胞间通讯和线粒体代谢在糖尿病肾病发病机制中的作用