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MicroRNA In Diabetic Nephropathy

糖尿病肾病中的 MicroRNA

基本信息

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
项目类别：
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

项目摘要

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/文摘