Non-junctional roles of desmosome proteins in the pathogenesis of arrhythmogenic cardiomyopathy
桥粒蛋白在致心律失常性心肌病发病机制中的非连接作用
基本信息
- 批准号:10705361
- 负责人:
- 金额:$ 50.16万
- 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:2022-09-22 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseAdultAffectAmino AcidsAngiotensin II ReceptorAnti-Inflammatory AgentsApoptosisArrhythmiaArrhythmogenic Right Ventricular DysplasiaBindingBinding SitesCRISPR/Cas technologyCardiacCardiac MyocytesCardiovascular DiseasesCause of DeathChromatinClinicalCloningComplexDesmosomesDisease modelDown-RegulationDystrophinElementsGene MutationGenesGeneticGenetic TranscriptionHeartHeart DiseasesHistone Deacetylase InhibitorHumanHyperactivityHypertensionIn VitroIndomethacinInfiltrationInsulinInsulin ReceptorInsulin ResistanceKnock-outLeadLuciferasesMediatingMembraneMessenger RNAMetabolicMetabolismMethodsMicroRNAsModelingMutationMyocardial dysfunctionNaturePPAR alphaPPAR gammaPathogenesisPathogenicityPathologicPathologyPathway interactionsPatientsPeroxisome Proliferator-Activated ReceptorsPharmaceutical PreparationsPoint MutationProlinePromoter RegionsPropertyProteinsProtocols documentationRight ventricular structureRoleSamplingSchemeSignal PathwaySignal TransductionSiteSite-Directed MutagenesisSodium ChannelSomatic CellSteroidsSudden DeathSystemTestingTherapeuticTherapeutic AgentsTherapeutic StudiesTimeTissuesToxic effectTrichostatin ATryptophanTyrosineanalogarrhythmogenic cardiomyopathybasebeta catenincaveolin-2caveolin-3clinical efficacyclinically relevantfatty acid oxidationhuman modelin vitro Modelin vivo Modelinduced pluripotent stem cellinduced pluripotent stem cell derived cardiomyocytesinherited cardiomyopathyinhibitorinnovationinsightinsulin signalinglipid biosynthesismouse modelmutantnew therapeutic targetnovelnovel therapeutic interventionnovel therapeuticsnucleocytoplasmic transportpatch clampplakoglobinplakophilin 2promoterrosiglitazoneside effecttranscription factorvalsartanvectoryoung adult
项目摘要
PROJECT SUMMARY
Cardiovascular diseases remain the major cause of death in the US. Recent advances in reprogramming
somatic cells from cardiac patients into induced pluripotent stem cells (iPSCs) enables in vitro modeling of
human cardiac diseases for pathogenic studies and therapeutic screens. Traditionally, weakened desmosome
junctions are considered the main pathogenic mechanism for Arrhythmogenic Cardiomyopathy (AC), caused
by mutations in five desmosome component proteins. Pathological hallmarks of AC are progressive fibro-fatty
replacement of cardiomyocytes (CMs) with increased CM apoptosis primarily in the RV, leading to sudden
death in the young. We have established a novel method to induce adult-like, fatty acid oxidation-dominant
metabolism of primitive CMs derived from iPSCs (iPSC-CMs) and established the first metabolic maturation-
based in vitro cardiac disease model for elucidation of novel pathogenic insights for human AC (Nature, 2013).
We showed that abnormal PPARγ activation after normal PPARα-mediated metabolic maturation in AC CMs
resulted in exaggerated lipogenesis, apoptosis, sodium channel deficits and defective Ca2+ handling in CMs
with desmosome mutations, recapitulating the pathological signatures of AC hearts. Using our AC model and
samples from pathological human AC hearts, we show here that plakoglobin is a key component of Insulin-p85
metabolic signaling complex. Desmosome mutations lead to faster plakoglobin degradation, reduce PI3K/Akt
activation, and hyperactivate GSK3β, which downregulate a microRNA (miR) cluster leading to subsequent
abnormal PPARγ activation and CM apoptosis. Importantly, we used genetic and cellular methods to confirm
the clinically relevance of our pathogenic pathways in human AC hearts and in mouse models of AC. We
propose here to further elucidate the dysregulated and non-junctional signaling networks caused by
plakoglobin deficits, to study how plakophilin-2 deficits deregulate additional signaling pathways, and to find
clinically safe therapeutic agents for treating AC using both in vitro iPSC-CM based models and mouse models
of AC.
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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HUEI-SHENG Vincent CHEN其他文献
HUEI-SHENG Vincent CHEN的其他文献
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{{ truncateString('HUEI-SHENG Vincent CHEN', 18)}}的其他基金
Maturation of Normal and Disease-specific Human Stem Cell-derived Cardiomyocytes
正常和疾病特异性人类干细胞来源的心肌细胞的成熟
- 批准号:
7952509 - 财政年份:2010
- 资助金额:
$ 50.16万 - 项目类别:
Maturation of Normal and Disease-specific Human Stem Cell-derived Cardiomyocytes
正常和疾病特异性人类干细胞来源的心肌细胞的成熟
- 批准号:
8118810 - 财政年份:2010
- 资助金额:
$ 50.16万 - 项目类别:
Maturation of Normal and Disease-specific Human Stem Cell-derived Cardiomyocytes
正常和疾病特异性人类干细胞来源的心肌细胞的成熟
- 批准号:
8281434 - 财政年份:2010
- 资助金额:
$ 50.16万 - 项目类别:
Maturation of Normal and Disease-specific Human Stem Cell-derived Cardiomyocytes
正常和疾病特异性人类干细胞来源的心肌细胞的成熟
- 批准号:
8489332 - 财政年份:2010
- 资助金额:
$ 50.16万 - 项目类别:
Maturation of Normal and Disease-specific Human Stem Cell-derived Cardiomyocytes
正常和疾病特异性人类干细胞来源的心肌细胞的成熟
- 批准号:
8686923 - 财政年份:2010
- 资助金额:
$ 50.16万 - 项目类别:
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