Deciphering the role of a circadian lncRNA in cardiac remodeling
解读昼夜节律lncRNA在心脏重塑中的作用
基本信息
- 批准号:10442269
- 负责人:
- 金额:$ 71.68万
- 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 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AdultAffectAgeAlternative SplicingBindingCardiacCardiac MyocytesCardiac developmentCardiovascular DiseasesCell NucleusCell physiologyChemicalsChromatinChromatin StructureCircadian DysregulationCircadian RhythmsClinicalDataExhibitsExonsGene ExpressionGene Expression ProfilingGene Expression RegulationGenesGenetic TranscriptionGenomeHeartHeart DiseasesHeart failureHumanIn VitroIncidenceInfarctionInterventionKnockout MiceLeadMass Spectrum AnalysisModelingMolecularMusMyocardialMyocardial InfarctionMyocardiumNuclearPathologicPeriodicityPhasePoly AProtein IsoformsProteinsRNARNA SplicingRegulationRegulator GenesRegulatory PathwayRoleSeriesSiteSpliceosomesSplicing Regulation PathwayStressStructureTechniquesTestingTherapeuticTimeTranscriptTreatment FailureUntranslated RNAWorkbasebiological adaptation to stresscircadiancircadian regulationdesignexperimental studygain of functionheart functionin vivoinduced pluripotent stem cellischemic cardiomyopathymortalitymouse modelmutantnovelnovel strategiespostnatalpromoterresponsetargeted treatmenttranscriptome sequencingvector
项目摘要
Project Summary
Heart failure (HF) is associated with a 5-year mortality of 50% and the incidence is still rising with most
cases associated with ischemic cardiomyopathy. Identifying novel strategies to counteract cardiac pathological
remodeling post myocardial infarction (MI) is of urgent clinical need. Long non-coding RNAs (lncRNA) have
recently emerged as regulators of cardiac development and disease. However, the function of most lncRNAs
remains unknown.
We have characterized the first cardiac specific circadian lncRNA Circa, which affects cardiac remodeling
post MI through regulating alternative splicing. To better understand the molecular mechanisms of Circa and its
partner proteins in the heart, we propose the following specific aims: 1. Identify the RNA structures that are
required for Circa nuclear localization and interaction with spliceosome. We will use the state-of-the-art chemical
probing technique to define the secondary structure of Circa, then use structure mutants to identify its functional
motifs. 2. Determine whether Circa acts in trans and whether its function is dependent on its oscillatory
expression. We will unambiguously determine Circa function as a transcript by a series of “rescue” experiments
in the novel knock out mice we created. Time restricted expression will be used to test the necessity of the
oscillatory expression. 3. Define the molecular basis by which Circa affects splicing in the heart. Our preliminary
data suggests Circa may suppress splicing regulator hnRNPA1. We will test the functional interaction between
Circa and hnRNPA1 using a cardiac target gene we identified. We will further investigate the role of hnRNAPA1
in the post MI remodeling by identifying its splicing targets using eCLIPseq/RNAseq and test the function of
hnRNPA1 in vitro and in vivo. Completion of this proposal will have significant impact in understanding splicing
regulation in the heart during post MI pathological remodeling and potentially expand our therapeutic strategies
for HF treatment.
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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Lilei Zhang其他文献
Lilei Zhang的其他文献
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{{ truncateString('Lilei Zhang', 18)}}的其他基金
Deciphering the role of a circadian lncRNA in cardiac remodeling
解读昼夜节律lncRNA在心脏重塑中的作用
- 批准号:
10599336 - 财政年份:2022
- 资助金额:
$ 71.68万 - 项目类别:
Transcriptional regulation of cardiac pathological remodeling by REV-ERBα
REV-ERBα 对心脏病理重塑的转录调节
- 批准号:
9927666 - 财政年份:2019
- 资助金额:
$ 71.68万 - 项目类别:
Transcriptional regulation of cardiac pathological remodeling by REV-ERBα
REV-ERBα 对心脏病理重塑的转录调节
- 批准号:
10171416 - 财政年份:2019
- 资助金额:
$ 71.68万 - 项目类别:
Transcriptional regulation of cardiac pathological remodeling by REV-ERBα
REV-ERBα 对心脏病理重塑的转录调节
- 批准号:
10447818 - 财政年份:2019
- 资助金额:
$ 71.68万 - 项目类别:
Transcriptional regulation of cardiac pathological remodeling by REV-ERBα
REV-ERBα 对心脏病理重塑的转录调节
- 批准号:
10610880 - 财政年份:2019
- 资助金额:
$ 71.68万 - 项目类别:
Role of KLF15 in Circadian Regulation of Cardiac Ischemia
KLF15 在心脏缺血昼夜节律调节中的作用
- 批准号:
9032864 - 财政年份:2016
- 资助金额:
$ 71.68万 - 项目类别:
Role of KLF15 in Circadian Regulation of Cardiac Ischemia
KLF15 在心脏缺血昼夜节律调节中的作用
- 批准号:
9204850 - 财政年份:2016
- 资助金额:
$ 71.68万 - 项目类别:
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