Role of small RNAs in ischemic tissue repair
小RNA在缺血组织修复中的作用
基本信息
- 批准号:10736743
- 负责人:
- 金额:$ 58.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-01 至 2028-06-30
- 项目状态:未结题
- 来源:
- 关键词:AccountingAcuteAlternative SplicingAngiogenic ProteinsApoptosisAttenuatedBinding SitesBiochemicalCardiacCardiac MyocytesCardiovascular DiseasesCardiovascular systemCause of DeathCell DeathCell ProliferationCell SurvivalCell physiologyCellsCessation of lifeDataDevelopmentDiagnosisEndothelial CellsGuide RNAHeartHeart InjuriesHeart failureHypoxiaImpairmentIn VitroInduction of ApoptosisInfarctionInnovative TherapyIschemiaKnowledgeLeft Ventricular FunctionLengthMass Spectrum AnalysisMediatingMessenger RNAMethylationModelingModificationMolecularMusMyocardial InfarctionMyocardial IschemiaMyocardial dysfunctionNephroblastomaNucleotidesOutcomePatientsPatternPlayPost-Transcriptional RegulationProcessPrognosisPublic HealthQuality of lifeRNARegimenReperfusion InjuryRiboseRoleSmall Nuclear RNASmall Nucleolar RNASmall RNASpliceosomesStressTestingTherapeuticTubeU4 Small Nuclear RibonucleoproteinsU4 small nuclear RNAUnited StatesUntranslated RNAWT1 geneangiogenesiscadherin 5cardiac repaircardiogenesiscardioprotectioncardiovascular disorder therapyeffective therapyextracellular vesiclesgain of functionheart functionimprovedin vivoinduced pluripotent stem cellinduced pluripotent stem cell derived cardiomyocytesinjury and repairinnovationinsightknock-downmigrationmutantmyocardial injuryneovascularizationnew therapeutic targetnovelnovel diagnosticsnovel therapeuticsoverexpressionparacrineposttranscriptionalpreservationpromoterrepairedreparative capacitytherapeutic RNAtherapeutic angiogenesistissue repairtooltranscriptome sequencingtreatment strategy
项目摘要
PROJECT SUMMARY
Cardiovascular disease (CVD) remains the leading cause of death, and there is a critical need to determine
underlying mechanisms and develop novel therapies for treatment. Small Cajal body-specific RNAs (scaRNAs)
are evolutionarily conserved non-coding RNAs that guide biochemical modification on specific nucleotides such
as pseudouridylation (Ψ) and 2′-O-ribose methylation (2′-OMe). These modifications are essential in the post-
transcriptional changes and functions of spliceosomal small nuclear RNAs (snRNA). Recent studies highlight a
crucial role of scaRNA in preserving spliceosome fidelity and cardiac development; however, the role of scaRNAs
in acute cardiac injury and its repair has not been established.
This
proposal aims to determine scaRNA’s role
in cardiovascular processes in a mouse myocardial infarction (MI) model that could develop new tools for treating
MI. Our central hypothesis is that overexpression of scaRNA18 in the post-MI heart promotes positive cardiac
remodeling by inducing therapeutic angiogenesis via 2′-OMe of U4 snRNA and regulating Wilms tumor1 (WT1)
expression, thereby conferring cardioprotection and improving cardiac function. Our preliminary data
demonstrates 1) decreased scaRNA18 expression in post-MI mouse hearts using unbiased small RNA
sequencing, 2) scaRNA18 expression exclusively downregulated in isolated cardiac endothelial cells (EC) in
post-MI mouse hearts, 3) scaRNA18 knockdown (KD) impairs tube formation and induces apoptosis in mouse
cardiac ECs without induced stress, 4) scaRNA18 overexpression enhances EC angiogenesis and inhibits
stress-induced EC apoptosis in vitro, 5) scaRNA18-overexpressing cardiac EC extracellular vesicles protect
iPSC-cardiomyocyte cell death via angiogenic proteins, 6) 2’-O-methylation levels were reduced in MI hearts
and in cardiac ECs from scaRNA18 KD mice, 7) mutant scaRNA18 lacking binding sites to guide 2′-OMe on U4
snRNA induces EC cell apoptosis without induced stress, 8) unbiased mass spectrometry results revealed that
scaRNA18 reduces WT1 expression levels in scaRNA18 KD cardiac ECs, 9) WT-1 KD in the presence of
scaRNA18 overexpression nullified scaRNA18 mediated EC survival effects, and 10) overexpression of
scaRNA18 by VE-cadherin-driven AAV9 reduces infarct size after ex vivo cardiac ischemia/reperfusion injury
and improves cardiac function post-MI mice (in vivo). The hypothesis that scaRNA18 is a critical component in
cardiac function and repair will be tested in the following three specific aims: in Aim 1, we will define the role of
scaRNA18 in cardiac EC function and cardiomyocyte survival; in Aim 2, we will determine the molecular
mechanisms by which scaRNA18 regulates cardiac EC function and cardiomyocyte survival, and in Aim 3 we
will use post-MI mice to demonstrate the critical role of scaRNA18 in myocardial injury repair. The proposed
studies could establish scaRNAs as novel therapeutic targets for MI.
项目总结
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A contemporary review of snoRNAs in cardiovascular health: RNA modification and beyond.
- DOI:10.1016/j.omtn.2023.102087
- 发表时间:2024-03-12
- 期刊:
- 影响因子:0
- 作者:Jagielski, Noah Peter;Rai, Amit Kumar;Rajan, K. Shanmugha;Mangal, Vatsal;Garikipati, Venkata Naga Srikanth
- 通讯作者:Garikipati, Venkata Naga Srikanth
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Venkata Naga Srikanth Garikipati其他文献
Long-lasting sex-specific alteration in left ventricular cardiac transcriptome following gamma and simGCRsim radiation
- DOI:
10.1038/s41598-025-89815-2 - 发表时间:
2025-02-18 - 期刊:
- 影响因子:3.900
- 作者:
Roksana Zakharyan;Siras Hakobyan;Agnieszka Brojakowska;Suren Davitavyan;Ani Stepanyan;Tamara Sirunyan;Gisane Khachatryan;Mary K. Khlgatian;Malik Bisserier;Shihong Zhang;Susmita Sahoo;Lahouaria Hadri;Venkata Naga Srikanth Garikipati;Arsen Arakelyan;David A. Goukassian - 通讯作者:
David A. Goukassian
Muscle-specific miR-499-5p delivered by small extracellular vesicles impairs endothelial function and ischemic hindlimb recovery in diabetic mice
- DOI:
10.1186/s12933-025-02825-2 - 发表时间:
2025-07-10 - 期刊:
- 影响因子:10.600
- 作者:
Zhongjian Cheng;May M. Truongcao;Vandana Mallaredy;Maria Cimini;Charan Thej;Darukeshwara Joladarashi;Carolina Gonzalez;Cindy Benedict;Suresh K. Verma;Venkata Naga Srikanth Garikipati;Raj Kishore - 通讯作者:
Raj Kishore
Evaluating sex-specific responses to western diet across the lifespan: impact on cardiac function and transcriptomic signatures in C57BL/6J mice at 530 and 640/750 days of age
- DOI:
10.1186/s12933-024-02565-9 - 发表时间:
2024-12-28 - 期刊:
- 影响因子:10.600
- 作者:
Ani Stepanyan;Agnieszka Brojakowska;Roksana Zakharyan;Siras Hakobyan;Suren Davitavyan;Tamara Sirunyan;Gisane Khachatryan;Mary K. Khlgatian;Malik Bisserier;Shihong Zhang;Susmita Sahoo;Lahouaria Hadri;Amit Rai;Venkata Naga Srikanth Garikipati;Arsen Arakelyan;David A. Goukassian - 通讯作者:
David A. Goukassian
Venkata Naga Srikanth Garikipati的其他文献
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