RNA editing controls pulmonary endothelial pathophenotypes in pulmonary hypertension
RNA编辑控制肺动脉高压的肺内皮病理表型
基本信息
- 批准号:10701669
- 负责人:
- 金额:$ 10.6万
- 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:2022-09-10 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdenosineAffectApoptosisApoptoticBindingBiological AssayBiologyBloodBlood VesselsCRISPR/Cas technologyCell SurvivalCell physiologyCellsCessation of lifeClinicalCodeComplexDataDependovirusDevelopmentDiagnosticDiseaseDouble-Stranded RNAElementsEndothelial CellsEndotheliumEnsureEnzymesEventFailureFoundationsFunctional disorderGene Expression RegulationGenesGenomeHealthHomeostasisHypoxiaIL6 geneImmunityImmunoprecipitationIn VitroInosineInterdisciplinary StudyInterferonsKnock-outKnockout MiceKnowledgeLungMedialMediatingMentorshipMessenger RNAMolecularMolecular TargetMusNatural ImmunityNucleic AcidsOutcomePECAM1 genePathogenesisPathway interactionsPatientsPeripheralPhysiologyPilot ProjectsPlayPost-Transcriptional RegulationProductionProteinsPulmonary HypertensionRNARNA EditingRNA SequencesRNA-Binding ProteinsRegulationResearchResearch PersonnelRight Ventricular HypertrophyRoleScientistSerumSignal TransductionSiteSmall Interfering RNAStructureStructure of parenchyma of lungSystolic PressureTestingTherapeuticThickTrainingTranscriptTransgenic MiceUntranslated RNAVascular remodelingVentricularWorkcareercareer developmentcell injurycell typecircadiandsRNA adenosine deaminaseexperimental studyheart functionhemodynamicshypoxia-induced pulmonary hypertensionin vivoinhibitorknock-downmRNA DecaymRNA ExpressionmRNA Stabilitymutantnocturninnovelnovel strategiesoverexpressionpharmacologicposttranscriptionalprogramspulmonary arterial pressurepulmonary artery endothelial cellpulmonary vascular disorderpulmonary vascular remodelingrepairedresponseright ventricular failuresingle-cell RNA sequencingtherapeutically effectivetranscription factortranscriptome sequencing
项目摘要
ABSTRACT
The primary objective of this proposal is to generate a scientific discovery program in pulmonary vascular disease
to ensure a robust pathway for Dr. Woodcock to develop into an independent research scientist. This objective
will be accomplished through a combination of active mentorship, didactic training, enrichment activities, and
research. The core of the research focuses on the role of RNA editing, a post-transcriptional regulation
mechanism, in pulmonary hypertension. Pulmonary hypertension (PH) is a lethal disease without a cure. Early
apoptosis in pulmonary artery endothelial cells (PAECs) is a key trigger for the development of PH. However,
there is a critical knowledge gap regarding the mechanisms or key factors controlling PAEC pathophenotypes
that drive this deadly disease, and no effective therapeutics exist for PH that target this key cell type.
Adenosine deaminase acting on RNA 1 (ADAR1) is a double-stranded RNA editing enzyme that converts
adenosine to inosine (A-to-I) in genome-encoded RNA transcripts and plays a vital role in gene regulation and
cardiac function. However, the roles of ADAR1-mediated RNA editing in the regulation of pulmonary vascular
function are unknown. Our preliminary data indicate that ADAR1 plays a crucial role in the regulation of PAEC
survival and the cytosolic innate immunity response. To identify enriched genes in PAECs that are modified and
regulated by ADAR1 RNA editing activity, we recently performed in vitro RNA sequencing in ADAR1 knockdown
PAECs. From this analysis, we found that the circadian gene nocturnin (NOCT) contains two active ADAR1 RNA
editing sites. Non-edited NOCT transcript is stable and accumulates within PAECs lacking ADAR1 RNA editing.
Forced expression of NOCT upregulated key interferon transcriptional factor IRF7 and promoted apoptosis in
PAECs. NOCT knockout (KO) mice mitigated PH induced by hypoxia and IL6 exposure. Lastly, silenced NOCT
restored PAEC apoptosis and immunity response triggered by ADAR1 deficiency. In our pilot studies, we
explored key elements of this concept by showing that ADAR1 RNA editing can control NOCT expression to
regulate PAEC functions and PH. Given these findings, we hypothesize that ADAR1 RNA editing deficiency
promotes PH development due to induction of pulmonary artery endothelial cell apoptosis via aberrant NOCT-
driven innate immunity activation. This hypothesis will be addressed in the experiments of the following Specific
Aims: (1) to determine the role of NOCT in the innate immunity-dependent PAEC survival response; (2) to
determine the effect of ADAR1-specific RNA editing on NOCT expression and function in PAECs; and (3) to
define the impact of endothelial ADAR1 deficiency on NOCT-IFN signaling in PH in vivo. This novel mechanism
may have important implications for how RNA editing regulates PA endothelial functions related to PH
pathogenesis, and its elucidation will advance our understanding of PH development and ultimately lead to novel
strategies for developing effective therapeutics to treat PH. This project will provide me with advanced expertise
in RNA biology and pulmonary physiology that will strengthen my development into an independent investigator.
摘要
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-Shan Julia Woodcock其他文献
Chen-Shan Julia Woodcock的其他文献
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{{ truncateString('Chen-Shan Julia Woodcock', 18)}}的其他基金
RNA editing controls pulmonary endothelial pathophenotypes in pulmonary hypertension
RNA编辑控制肺动脉高压的肺内皮病理表型
- 批准号:
10350176 - 财政年份:2022
- 资助金额:
$ 10.6万 - 项目类别:
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