Gene Modulation of Acetylation Modifiers to Reveal Regulatory Links to Human Cardiac Electromechanics
乙酰化修饰剂的基因调节揭示与人类心脏机电的调节联系
基本信息
- 批准号:10677295
- 负责人:
- 金额:$ 3.79万
- 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:2023-06-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AcetylationAction PotentialsAcuteArrhythmiaAutoimmune DiseasesAutomobile DrivingAutophagocytosisBehaviorBiological AssayCRISPR interferenceCRISPR-mediated transcriptional activationCalciumCardiacCardiac Electrophysiologic TechniquesCardiac healthCardiotoxicityCardiovascular DiseasesCardiovascular systemCell CycleCellsComplexComputer ModelsContractile ProteinsCytoskeletal ProteinsDataDevelopmentDisease modelElectrophysiology (science)Emergency SituationEpigenetic ProcessEventExhibitsFeedbackFibrosisFrequenciesFunctional disorderGene ExpressionGenesGenetic TranscriptionGuide RNAHealthHeartHeart InjuriesHistone DeacetylaseHistone Deacetylase InhibitorHomeostasisHumanHypertrophyImmune System DiseasesIndividualInflammatory ResponseInterventionIon ChannelIschemiaLibrariesLinkMalignant NeoplasmsMeasurementMeasuresMechanicsMitochondriaModelingMorbidity - disease rateOncologyOpticsOxidative StressPathologyPhenotypePredispositionProcessProteinsPublic HealthRNA InterferenceRegulationRegulator GenesReperfusion InjuryRepressionResearchRoleSamplingShapesSmall Interfering RNASpecificityStimulusTechniquesTherapeuticTissuesUnited StatesValidationVariantWorkcancer therapycardioprotectionchromatin remodelingcost estimateepigenetic regulationepigenomicsexperienceexperimental studygene regulatory networkgene repressionheart functionimprovedinduced pluripotent stem cell derived cardiomyocytesinterestknock-downloss of functionmortalitymouse modelnovelpatient prognosispharmacologicresponsescreeningtooltranscription factortranscriptome sequencingtranscriptomic profilingtranscriptomicstumor progressionvoltage
项目摘要
PROJECT ABSTRACT
Epigenetic regulation is critical for cardiac electromechanics and pathology. Epigenetic modulators, such as
histone deacetylases (HDACs), are known master regulators of gene expression and influence cardiac function
through chromatin remodeling, direct action on transcription factors (TFs), and action on cytoskeletal and
contractile proteins, among others. Recently, novel pharmacological agents, HDAC inhibitors, have been
developed as treatments for cancer and immune diseases, driving an interest in robust characterization of HDAC
control in cardiac function. Our preliminary experiments focused on computational modeling of RNAi-informed
transcriptomic data in human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM) but saw
limitations in knockdown efficiency and loss-of-function-only modulation using siRNAs. To extend and improve
this work, we propose an experimental approach based on bidirectional perturbation (repression/activation) of
individual HDAC genes in hiPSC-CM by CRISPR interference and activation (CRISPRi/a). Transcriptomic
analysis of these samples will inform computational gene regulatory network (GRN) inference to model
relationships between HDACs, TFs, and cardiac ion channels. GRN-predicted relationships will be validated by
all-optical electromechanical assays measuring voltage, calcium, and contraction traces in hiPSC-CM. An
iterative approach will allow feedback from functional experiments to refine our computational models. Such
studies will advance our understanding of how certain HDACs drive electrophysiological phenotypes in the heart,
which is critical in the fields of cardiac injury, cardiac therapeutics, and cardio-oncology.
项目摘要
表观遗传调节对于心脏机电和病理学至关重要。表观遗传调节剂,例如
组蛋白脱乙酰基酶(HDACS)是基因表达的已知主要调节剂,并影响心脏功能
通过染色质重塑,直接对转录因子(TFS)作用以及对细胞骨架和细胞骨架的作用
收缩蛋白等。最近,新型的药理学剂,HDAC抑制剂已经是
开发为癌症和免疫疾病的治疗方法,引起了对HDAC鲁棒表征的兴趣
控制心脏功能。我们的初步实验着重于RNAi信息的计算建模
人类诱导多能干细胞衍生的心肌细胞(HIPSC-CM)中的转录组数据,但看到
使用siRNA的敲低效率和仅功能丧失调制的限制。扩展和改善
这项工作,我们提出了一种基于双向扰动(抑制/激活)的实验方法
HIPSC-CM中的单个HDAC基因通过CRISPR干扰和激活(CRISPRI/A)。转录组
对这些样品的分析将为计算基因调节网络(GRN)推论提供信息
HDAC,TFS和心脏离子通道之间的关系。 GRN预测的关系将由
HIPSC-CM中测量电压,钙和收缩痕迹的全光机电测定法。一个
迭代方法将允许功能实验的反馈来完善我们的计算模型。这样的
研究将促进我们对某些HDAC如何驱动心脏中的电生理表型的理解,
这对于心脏损伤,心脏治疗和心脏肿瘤学领域至关重要。
项目成果
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