MicroRNA In Diabetic Nephropathy
糖尿病肾病中的 MicroRNA
基本信息
- 批准号:10381348
- 负责人:
- 金额:$ 46.03万
- 依托单位:
- 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:
- 关键词:AddressAreaBinding ProteinsBiologicalBiological MarkersCarbohydratesCardiovascular PathologyCell NucleusCharacteristicsClinical ResearchCommunicationComplementCytoplasmDataDevelopmentDiabetes MellitusDiabetic NephropathyDiabetic mouseDiagnosticDiseaseExperimental ModelsFundingFutureGene ExpressionGenesGenetic TranscriptionGlucoseGoalsHomeostasisInvestigationKidneyLabelLaboratoriesMalignant NeoplasmsMediatingMedicalMedicineMicroRNAsMitochondriaModelingMolecularNon-Insulin-Dependent Diabetes MellitusNuclearNucleotidesOpen Reading FramesPPAR gammaPathogenesisPathologicPathologyPatientsPeptidesProcessPropertyProteinsPublishingRNARegulationResearchResponse ElementsRoleTaurineTechniquesTherapeuticTissuesTranscriptTransgenic MiceTranslatingUntranslated RNAWorkdb/db mousediabeticexpectationgenetic approachin vivomitochondrial fitnessmitochondrial metabolismmutant mouse modelneurological pathologynew therapeutic targetnext generationoverexpressionpodocyteprotective effectresponsetargeted treatmenttherapeutic targettranscription 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
项目成果
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