Targeting cardiac fibroblast-myocyte cross talk to enhance heart function after cardiac injury
靶向心脏成纤维细胞-肌细胞的串扰以增强心脏损伤后的心脏功能
基本信息
- 批准号:10471907
- 负责人:
- 金额:$ 54.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-02 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectAnimalsAreaAttenuatedBiochemicalCardiacCardiac MyocytesCardiovascular systemCell DeathCellsCicatrixCollaborationsDataDilatation - actionDiphosphatesEndothelial CellsEventFibroblastsFibrosisGeneticGoalsHeartHeart InjuriesHourInfarctionInfiltrationInflammationInflammatoryIntegral Membrane ProteinMediatingMediator of activation proteinMetabolicMolecularMolecular Mechanisms of ActionMonoclonal AntibodiesMuscle CellsMyocardial InfarctionMyocardial dysfunctionMyocardiumNatural regenerationNecrosisNuclear Magnetic ResonancePathway interactionsPharmaceutical ChemistryPharmaceutical PreparationsPharmacologyPhasePhysiologicalPlayPopulationProliferatingProteinsPublic HealthResearch PersonnelRoleSignal TransductionSmooth Muscle MyocytesStructureTestingTherapeuticTimeTissuesVentricularcalcificationcardiac repaircell typecytokineextracellularheart functionhemodynamicsinjuredischemic injuryloss of functionmacrophagemetabolomicsmonocytemyocardial injuryneutrophilnovelplasma cell membrane glycoprotein PC-1preservationpyrophosphataserepair functionrepairedresponse to injurysingle-cell RNA sequencingsmall moleculesmall molecule inhibitorspatiotemporalstem cellstreatment strategywound healing
项目摘要
Project Summary/Abstract
Cardiac repair following ischemic myocardial injury involves a carefully orchestrated set of cellular events. The
cardiac cell population substantially changes after cardiac injury with infiltration of initially neutrophils, then
macrophages and robust proliferation of fibroblasts and endothelial cells. Cell-cell cross talk undoubtedly
affects cardiac wound healing but little is known about whether cell-cell cross talk can be targeted for
enhancing cardiac repair. In this proposal, we identify an unusual cross talk between myocytes and non-
myocytes that regulates cardiac wound healing. We demonstrate that cardiac fibroblasts dramatically
upregulate the protein ENPP1 (ectonucleotide pyrophosphatase 1) following ischemic cardiac injury. ENPP1
hydrolyzes extracellular ATP and we show that ATP hydrolytic products induces myocytes to release
metabolites that are pro-inflammatory and induce cell death of various non-myocyte cells regulating wound
healing such as macrophages, endothelial cells, fibroblasts and smooth muscle cells. We identify such
myocyte secreted pro-inflammatory metabolites and investigate molecular mechanisms of action of such
metabolites on non-myocyte cells. We provide preliminary data that genetic deletion of ENPP1 in cardiac
fibroblasts dramatically ameliorates post injury heart function and is associated with decreased scarring and
decreased post injury cardiac dilatation. We identify small molecule inhibitors of ENPP1 as well as monoclonal
antibodies targeting ENPP1 and demonstrate that pharmacologic targeting of ENPP1 can serve as a
therapeutic strategy for post infarction cardiac remodeling. These observations form a rational basis for
investigating in depth the physiological significance of ENPP1 mediated myocyte-non myocyte cross talk in
cardiac repair and determine whether pharmacologic targeting of ENPP1 mediated fibroblast-non myocyte
cross talk is potentially a therapeutic strategy for ischemic cardiac injury.
项目总结/文摘
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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专利数量(0)
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Arjun Deb其他文献
Arjun Deb的其他文献
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{{ truncateString('Arjun Deb', 18)}}的其他基金
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用单克隆抗体靶向心脏中的核酸外切酶以预防梗死后心力衰竭
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10711469 - 财政年份:2023
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Identifying therapeutic strategies for the multisystem genetic disorder Pseudoxanthoma Elasticum
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Role of collagen heterogeneity in remodeling of acute and chronic heart scars
胶原异质性在急慢性心脏疤痕重塑中的作用
- 批准号:
10642804 - 财政年份:2020
- 资助金额:
$ 54.6万 - 项目类别:
Role of collagen heterogeneity in remodeling of acute and chronic heart scars
胶原异质性在急慢性心脏疤痕重塑中的作用
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10439439 - 财政年份:2020
- 资助金额:
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Role of collagen heterogeneity in remodeling of acute and chronic heart scars
胶原异质性在急慢性心脏疤痕重塑中的作用
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10202723 - 财政年份:2020
- 资助金额:
$ 54.6万 - 项目类别:
Identifying therapeutic strategies for the multisystem genetic disorder Pseudoxanthoma Elasticum
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9884160 - 财政年份:2020
- 资助金额:
$ 54.6万 - 项目类别:
Identifying therapeutic strategies for the multisystem genetic disorder Pseudoxanthoma Elasticum
确定多系统遗传性疾病弹性假黄瘤的治疗策略
- 批准号:
10092959 - 财政年份:2020
- 资助金额:
$ 54.6万 - 项目类别:
Targeting cardiac fibroblast-myocyte cross talk to enhance heart function after cardiac injury
靶向心脏成纤维细胞-肌细胞的串扰以增强心脏损伤后的心脏功能
- 批准号:
10685568 - 财政年份:2020
- 资助金额:
$ 54.6万 - 项目类别:
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