Novel Mechanism of RBFox1 Mediated RNA Metabolism in Heart Failure
RBFox1 介导心力衰竭 RNA 代谢的新机制
基本信息
- 批准号:10543715
- 负责人:
- 金额:$ 24.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:3&apos Untranslated RegionsAlternative SplicingAreaBindingBiologyCardiacCardiac MyocytesCardiologyCardiovascular DiseasesCell NucleusDevelopment PlansDiseaseDisease ProgressionEventFoundationsFunctional disorderFutureGene DeliveryGene ExpressionGene Expression RegulationGenesGeneticGenetic TranscriptionGoalsHeartHeart DiseasesHeart HypertrophyHeart failureIn VitroInflammatoryKnowledgeLeadMediatingMessenger RNAMicroRNAsMolecularMolecular AnalysisMusMuscleMuscle CellsMyocardial InfarctionNuclearOrganOutcomePathogenesisPathologicPathologyPhasePhysiologyPlayPost-Transcriptional RegulationProcessProtein IsoformsProteinsRNARNA DecayRNA ProcessingRNA SplicingRNA metabolismRNA-Binding ProteinsRegulationReperfusion InjuryReportingResearchResearch PersonnelRibosomesRoleStressSupervisionTestingTetanus Helper PeptideTransgenic MiceTranslationsUnited StatesVariantbasecareercareer developmentcoronary fibrosiscrosslinking and immunoprecipitation sequencingexperimental studyfetalgene repressionheart functionin vivoinsightmRNA Decaymouse modelnovelpost-doctoral trainingpressureresponseribosome profilingskillstherapeutic targettranscriptome
项目摘要
PROJECT SUMMARY
RNA metabolism from synthesis, processing, translation to degradation is an integrated part of gene
regulation that ultimately determines the overall cardiac transcriptome complexity and reprogramming during
heart failure. RNA binding proteins are central to every process of RNA metabolism and therefore establishing
their roles in the onset and progression of heart failure should lead to novel disease mechanisms and potential
therapeutic targets. Earlier reports by the PI (Dr. Chen Gao) have revealed that global RNA splicing changes
are important part of cardiac transcriptome reprogramming in failing heart. Furthermore, this fetal-like RNA-
splicing reprogramming is regulated by RBFox1, a muscle enriched RNA splicing factor. However, in new study,
PI found cardiac RBFox1 gene also encoded a cytosolic isoform (RBFox1c) due to its own alternative mRNA
splicing. While the nuclear RBFox1n contributes to cardiac hypertrophic response through global alternative
splicing regulation as demonstrated by the PI, the functional role of the cytosolic RBFox1c in cardiac pathology
is yet to be explored. In preliminary studies both in vitro and in vivo, PI found the cytosolic RBFox1c played a
critical role in cardiac remodeling associated with reduced pro-inflammatory gene expression in stressed heart
muscle cells. This proposal aims at characterizing the non-canonical function of RBFox1c in cardiac disease
progression and exploring the RBFox1c mediated post-transcriptional regulatory mechanism in heart. It also
outlines an extensive career development plan for Dr. Chen Gao to complete postdoctoral training under the
supervision of Dr. Yi Xing and to transition into an independent investigator well equipped with a unique
combination of research skills, scientific insights and highly promising research pipeline.
During the K99 phase of this proposal, the PI will characterize the functional impact of RBFox1c in cardiac
fibrotic response using both genetic mouse model and in vitro cultured cardiomyocytes. The second aim of the
K99 phase is to determine the molecular mechanism of RBFox1c mediated inflammatory gene repression.
During the R00 phase, the PI will characterize isoform specific impact of RBFox1 in cardiac physiology and
pathological remodeling using isoform specific manipulated mouse models. The PI will also explore the post-
transcriptional regulatory mechanisms mediated by RBFox1c in heart through BRIC-Seq, TRAP ribo-seq and
microRNA competition analysis. The proposed experiments will create exciting new opportunities of fundamental
discovery in an important yet vastly under-explored area in cardiac biology, and new insight will also fill an
important gap in the current understanding to the pathogenesis of cardiac remodeling induced by pathological
stress.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Chen Gao其他文献
Chen Gao的其他文献
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{{ truncateString('Chen Gao', 18)}}的其他基金
Novel Mechanism of RBFox1 Mediated RNA Metabolism in Heart Failure
RBFox1 介导心力衰竭 RNA 代谢的新机制
- 批准号:
10589838 - 财政年份:2022
- 资助金额:
$ 24.9万 - 项目类别:
Novel Mechanism of RBFox1 Mediated RNA Metabolism in Heart Failure
RBFox1 介导心力衰竭 RNA 代谢的新机制
- 批准号:
10369072 - 财政年份:2019
- 资助金额:
$ 24.9万 - 项目类别:
Novel Mechanism of RBFox1 Mediated RNA Metabolism in Heart Failure
RBFox1 介导心力衰竭 RNA 代谢的新机制
- 批准号:
9898447 - 财政年份:2019
- 资助金额:
$ 24.9万 - 项目类别:
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