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
基本信息
- 批准号:10642804
- 负责人:
- 金额:$ 50.7万
- 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:2020-07-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAcute myocardial infarctionAffectAnimalsAtomic Force MicroscopyAutomobile DrivingBiomedical EngineeringCardiacCardiac healthCardiovascular systemCellsChemicalsChronicCicatrixClinical ResearchCollagenCollagen FibrilCollagen Type IIICollagen Type VDataDilatation - actionExtracellular MatrixExtracellular Matrix ProteinsFamilyFibrillar CollagenFibroblastsFibrosisFluorescent in Situ HybridizationGene ExpressionGenesGeneticHeartHeart InjuriesHeterogeneityIndividualInfarctionIntegrinsMapsMechanicsMediatingMinorMolecularMusMyocardialMyocardial InfarctionMyocardial IschemiaMyocardiumMyofibroblastNatural regenerationOutcomePatientsPhenotypePhysiologicalPlayPropertyProtein SecretionProteomicsPublic HealthRNARegulationRoleSecondary toSignal TransductionSmooth MuscleStressTechniquesTherapeuticTissuesTransmission Electron MicroscopyVentricular Remodelingcardiac repairhealingheart dimension/sizeheart functionheart imaginghemodynamicsin vivoischemic injuryloss of functionmechanical propertiesmortalitynovelpressurerepairedresponsespatiotemporaltissue support frametranscriptomicswound healing
项目摘要
Project Summary/Abstract
The mammalian heart possesses a poor ability to regenerate after ischemic cardiac injury and heals via scar
formation. Multiple clinical studies have demonstrated that the size of scar tissue is an independent predictor of
cardiovascular outcomes and mortality after acute myocardial infarction. However, little is understood about
factors that regulate the degree of fibrosis or size of scar tissue after acute ischemic cardiac injury. Collagens
are the most differentially upregulated genes following ischemic cardiac injury and remain the most abundant
form of extracellular matrix (ECM) proteins secreted in the infarcted heart. Type I and III collagens are the
principal collagens found in the heart but we show that a large number of collagens that are minimally
expressed in the uninjured heart are robustly induced following ischemic cardiac injury. In this proposal, we
investigate the physiological necessity of collagen heterogeneity and demonstrate that type V collagen, a
fibrillar collagen plays a critical role in regulating the size of scar tissue after ischemic cardiac injury. Using
multiplexing of RNA-FISH (fluorescence in situ hybridization) or MERFISH, we create a collagen map of the
heart and use genetic loss of function techniques to determine the functional significance of type V collagen in
regulating the size of post infarct scar tissue and heart function. We determine how the chemical composition
of ECM changes following type V collagen deletion, study the mechano-biological properties of altered matrix
and examine how such changes affect cardiac function and distribution of myocardial wall stress. We dissect
the molecular mechanisms mediating regulation of scar size by type V collagen. We demonstrate that type V
collagen deletion is associated with profound activation of cardiac fibroblasts in the infarcted heart and show
that augmented myofibroblast activation is secondary to an altered integrin expression profile on cardiac
fibroblasts. We study the mechanisms of altered integrin expression, integrin mediated mechanisms driving
myofibroblast activation and determine whether inhibition of specific integrins can rescue the phenotype of
increased post infarct scarring observed in type V collagen deficient states. Taken together, our proposal will
lead to a broader understanding of cardiac wound healing and illustrate a new paradigm of cardiac repair
where the structural constituents of heart scars regulate the size of scar itself.
项目总结/摘要
哺乳动物的心脏在缺血性心脏损伤后再生能力差,通过瘢痕愈合
阵多项临床研究表明,瘢痕组织的大小是一个独立的预测因子,
急性心肌梗死后的心血管结局和死亡率。然而,人们对
调节急性缺血性心脏损伤后纤维化程度或瘢痕组织大小的因素。胶原
是缺血性心脏损伤后差异上调最多的基因,
细胞外基质(ECM)蛋白质的一种形式,在梗塞的心脏中分泌。I型和III型胶原蛋白是
心脏中发现的主要胶原蛋白,但我们表明,大量的胶原蛋白,
在缺血性心脏损伤后,在未损伤心脏中表达的蛋白质被强烈诱导。在本提案中,我们
研究胶原蛋白异质性的生理必要性,并证明V型胶原蛋白,
纤维状胶原蛋白在调节缺血性心脏损伤后瘢痕组织的大小方面起关键作用。使用
多重RNA-FISH(荧光原位杂交)或MERFISH,我们创建了一个胶原蛋白的地图,
心脏,并使用遗传功能丧失技术,以确定V型胶原蛋白的功能意义,
调节梗死后瘢痕组织的大小和心脏功能。我们确定化学成分是如何
的ECM变化后,V型胶原删除,研究改变基质的力学生物学特性
并研究这些变化如何影响心脏功能和心肌壁应力分布。我们解剖
通过V型胶原调节瘢痕大小的分子机制。我们证明V型
胶原缺失与梗塞心脏中心脏成纤维细胞的深度激活有关,
增强的肌成纤维细胞活化是继发于心肌细胞上整合素表达谱的改变,
成纤维细胞我们研究了整合素表达改变的机制,整合素介导的驱动机制,
肌成纤维细胞活化,并确定特异性整合素的抑制是否可以挽救肌成纤维细胞的表型。
在V型胶原缺乏状态下观察到梗死后瘢痕形成增加。综合考虑,我们的建议将
导致对心脏伤口愈合更广泛的理解,并阐明了心脏修复的新范例
其中心脏疤痕的结构成分调节疤痕本身的大小。
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Association of serum HDL-cholesterol and apolipoprotein A1 levels with risk of severe SARS-CoV-2 infection.
- DOI:10.1016/j.jlr.2021.100061
- 发表时间:2021
- 期刊:
- 影响因子:6.5
- 作者:Hilser JR;Han Y;Biswas S;Gukasyan J;Cai Z;Zhu R;Tang WHW;Deb A;Lusis AJ;Hartiala JA;Allayee H
- 通讯作者:Allayee H
DDR2, a discoidin domain receptor, is a marker of periosteal osteoblast and osteoblast progenitors.
DDR2 是一种盘状结构域受体,是骨膜成骨细胞和成骨细胞祖细胞的标记物
- DOI:10.1007/s00774-020-01108-y
- 发表时间:2020-09
- 期刊:
- 影响因子:3.3
- 作者:Yang H;Sun L;Cai W;Gu J;Xu D;Deb A;Duan J
- 通讯作者:Duan J
Fibroblasts in heart scar tissue directly regulate cardiac excitability and arrhythmogenesis.
心脏疤痕组织中的成纤维细胞直接调节心脏兴奋性和心律失常发生。
- DOI:10.1126/science.adh9925
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Wang,Yijie;Li,Qihao;Tao,Bo;Angelini,Marina;Ramadoss,Sivakumar;Sun,Baiming;Wang,Ping;Krokhaleva,Yuliya;Ma,Feiyang;Gu,Yiqian;Espinoza,Alejandro;Yamauchi,Ken;Pellegrini,Matteo;Novitch,Bennett;Olcese,Riccardo;Qu,Zhilin;Song,Zh
- 通讯作者:Song,Zh
Cardiomyocytes disrupt pyrimidine biosynthesis in nonmyocytes to regulate heart repair.
- DOI:10.1172/jci149711
- 发表时间:2022-01-18
- 期刊:
- 影响因子:0
- 作者:Li S;Yokota T;Wang P;Ten Hoeve J;Ma F;Le TM;Abt ER;Zhou Y;Wu R;Nanthavongdouangsy M;Rodriguez A;Wang Y;Lin YJ;Muranaka H;Sharpley M;Braddock DT;MacRae VE;Banerjee U;Chiou PY;Seldin M;Huang D;Teitell M;Gertsman I;Jung M;Bensinger SJ;Damoiseaux R;Faull K;Pellegrini M;Lusis AJ;Graeber TG;Radu CG;Deb A
- 通讯作者:Deb A
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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:
$ 50.7万 - 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:
$ 50.7万 - 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:
$ 50.7万 - 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:
$ 50.7万 - 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:
$ 50.7万 - 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:
$ 50.7万 - 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:
10471907 - 财政年份:2020
- 资助金额:
$ 50.7万 - 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:
$ 50.7万 - 项目类别:
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