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.

项目概要/摘要 我们正在见证医学实践的范式转变，即靶向 RNA 的概念 随着诊断和治疗策略的迅速发展。 Lon 非编码 RNA (lncRNA) 是一种高度 参与基因几乎每个阶段调控的异质非编码转录本组 表达，以及参与多种疾病状态。几种lncRNA的失调 也与糖尿病肾病 (DN) 的进展有关，并且由于组织特异性 lncRNA的特征，它们被认为是下一代生物标志物并且有前途 DN 进展的治疗靶点 在上一个资助周期中，我们的实验室提供了强有力的证据，表明 lncRNATug1 在几个方面被下调 DN 和 2 型糖尿病患者的实验模型（Long 等人，JCI，2016）。重要的是， 足细胞中 Tug1 的条件性过度表达可减轻 DN 的进展。我们还发表了我们的研究结果 证明 Tug1 介导的 DN 肾脏保护是通过 PGC1a 依赖的 线粒体功能的机制。因此，我们提出Tug1作为一个新的治疗靶点 DN 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 通过细胞核中 PGC1a 依赖性机制间接影响线粒体功能，2) 我们现在提供初步数据表明 Tug1 也从细胞核易位到线粒体。 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 转录物定位于细胞质，被翻译成微肽。一些 lncRNA 已被证明可以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 Tug1 编码的微肽对 线粒体功能。然而，其对线粒体稳态和 DN 进展的作用尚不清楚。 在此应用中，我们提出了 Tug1 介导的线粒体重塑影响的收敛模型 在 DN 中。将解决两个基本问题：1）首先，阐明亚细胞分布和 线粒体相关 Tug1 (mitoTug1) 对线粒体稳态和 DN 进展的功能， 2) 其次，确定 Tug1 编码的微肽对 线粒体功能和 DN 进展。我们将描述研究的各种技术和策略 Tug1 对线粒体重塑的潜在作用、这些方法面临的挑战以及我们发表的和 初步数据。我们的申请的成功完成将高度重视制定策略 将Tug1作为未来临床研究的潜在候选者，并为该研究开辟丰富的领域 DN 发病机制中的细胞器间通讯和线粒体代谢。