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.
项目摘要/摘要
缺血性心肌损伤后的心脏修复涉及一系列精心策划的细胞事件。这个
心脏损伤后心肌细胞数量发生了实质性变化,最初有中性粒细胞的渗透,然后
巨噬细胞和成纤维细胞和内皮细胞的旺盛增殖。毫无疑问,细胞间的串扰
影响心脏伤口的愈合,但细胞间的串扰是否可以作为靶点尚不清楚。
加强心脏修复。在这个提议中,我们确定了心肌细胞和非心肌细胞之间的一种不寻常的串扰
调节心脏伤口愈合的肌细胞。我们证明心脏成纤维细胞戏剧性地
在缺血性心脏损伤后上调ENPP1蛋白(外核苷酸焦磷酸酶1)。ENPP1
水解胞外三磷酸腺苷,我们发现三磷酸腺苷水解物诱导心肌细胞释放
促炎代谢产物,可诱导多种非心肌细胞调节伤口的细胞死亡
巨噬细胞、内皮细胞、成纤维细胞和平滑肌细胞等的愈合。我们确定了这样的
心肌细胞分泌促炎代谢物及其分子作用机制的研究
非心肌细胞上的代谢物。我们提供了心脏组织中ENPP1基因缺失的初步数据
成纤维细胞可显著改善损伤后的心功能,并与减少瘢痕形成和
损伤后心脏扩张减少。我们鉴定了ENPP1的小分子抑制剂以及单抗
针对ENPP1的抗体,并证明ENPP1的药理学靶向可以作为一种
心肌梗死后心脏重构的治疗策略。这些观察形成了一个合理的基础
深入探讨ENPP1介导的心肌细胞-非心肌细胞串扰的生理意义
心脏修复及确定ENPP1介导的成纤维细胞-非心肌细胞是否具有药理靶向性
串扰是一种潜在的治疗缺血性心脏损伤的策略。
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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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
Targeting a ectonucleotidase in the heart with a monoclonal antibody to prevent post-infarct heart failure
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
- 批准号:
10711469 - 财政年份:2023
- 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:
10311027 - 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
- 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
- 批准号:
10439439 - 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
- 批准号:
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
确定多系统遗传性疾病弹性假黄瘤的治疗策略
- 批准号:
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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