Role of GPNMB in cardiac remodeling
GPNMB 在心脏重构中的作用
基本信息
- 批准号:10521279
- 负责人:
- 金额:$ 68.8万
- 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:2020-12-20 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:Acute myocardial infarctionAdoptedAffectAntisense OligonucleotidesAttenuatedBindingBiologicalBiological MarkersBiological ModelsBiologyBone Marrow TransplantationCardiacCardiac MyocytesCardiovascular AgentsCellsCicatrixCirculationCollaborationsDataDependovirusDevelopmentDiagnosisDilatation - actionEventExtracellular DomainExtracellular MatrixFibroblastsFibrosisGPR39 geneGenesGeneticGlycoproteinsHeartHeart HypertrophyHeart InjuriesHeart failureHeparitin SulfateHumanHuman GeneticsHypertrophyInbred Strains MiceInfarctionInjuryIntegral Membrane ProteinIsoproterenolLigand BindingMacrophageMapsMediatingMitochondriaMusMuscle CellsMyocardial InfarctionMyocardiumNatural regenerationNonmetastaticOrphanPathway interactionsPeptide HydrolasesPharmacologic SubstancePhysiologicalPhysiologyPlasmaProteinsProteomicsPublic HealthRoleSignal PathwaySite-Directed MutagenesisSourceSystemTherapeuticTimeTissuesWild Type Mouseattenuationexperimental studygain of functiongenetic approachhealingheart functionheart preservationhemodynamicsin vivoinsightloss of functionmelanomamouse geneticsmouse modelmultidisciplinarynovelpharmacologicpressureprotein Breceptorrecruitrepairedresponsetraitwound healing
项目摘要
PROJECT SUMMARY/ABSTRACT
The mammalian heart has a poor ability to regenerate heart muscle following myocardial infarction and dead
cardiac muscle is replaced by scar tissue. Scar tissue is non-contractile, induces adverse cardiac remodeling
and leads to dilatation of cardiac chambers, cardiomyocyte hypertrophy and development of heart failure.
Despite optimal use of cardiovascular drugs, adverse remodeling following myocardial infarction contributes to
40% of all new case of heart failure. There thus exists an immense need to identify new targets for attenuating
post infarct remodeling and development of heart failure. In this application, we identify GPNMB (Glycoprotein
Non-Metastatic Melanoma Protein B) as a novel target for attenuating post infarct cardiac remodeling. We
identified the protein using a systems genetics approach, in which a panel of inbred strains of mice were
studied for heart failure traits in response to isoproterenol treatment. We demonstrate that GPNMB expression
increases by an order of magnitude in infarcted murine hearts and regulates wound healing events in the heart
early following injury. We show that macrophages that are recruited to the infarcted heart are the primary
source of GPNMB expression. Using loss and gain of function approaches, we demonstrate that GPNMB
activates cardiac fibroblasts and induces profound cardiomyocyte hypertrophy. In contrast, genetic deletion of
GPNMB leads to attenuation of post infarct cardiac remodeling and is associated with better preservation of
cardiac function. We also provide data that GPNMB plasma levels in humans is strongly associated with heart
failure strengthening a causal relationship between GPNMB and the development of post infarct heart failure.
Considering these observations, we hypothesize that GPNMB regulates (i) post infarct cardiac remodeling and
(ii) inhibition of GPNMB will attenuate post infarct cardiac remodeling. We have assembled a multi-disciplinary
team comprising expertise in cardiac physiology, genetics and extracellular matrix biology to interrogate the
role and mechanisms of GPNMB in regulating post infarct cardiac remodeling. In the first aim, we will examine
the role of GPNMB on cardiac remodeling with gain and loss of function approaches. In the second aim, we will
identify mechanisms of GPNMB activation and use physico-chemical studies to determine the receptor to
which GPNMB ligand binds and GPNMB domains critical for binding. In the third aim, we will use mouse and
human genetics approaches to model biological pathways influenced by GPNMB and interrogate common
downstream signaling pathways that mediate GPNMB effects on myocytes and non-myocytes. Finally, we will
determine whether pharmacological targeting of GPNMB can be therapeutic strategy for attenuating adverse
remodeling after cardiac injury.
项目概要/摘要
哺乳动物心脏在心肌梗塞和死亡后再生心肌的能力很差
心肌被疤痕组织取代。疤痕组织是非收缩性的,会引起不良的心脏重塑
并导致心室扩张、心肌细胞肥大和心力衰竭的发展。
尽管心血管药物得到了最佳使用,但心肌梗死后的不良重塑仍会导致
占所有新发心力衰竭病例的 40%。因此,迫切需要确定新的目标来减少
梗塞后重塑和心力衰竭的发展。在此应用中,我们识别 GPNMB(糖蛋白
非转移性黑色素瘤蛋白 B)作为减轻梗死后心脏重塑的新靶点。我们
使用系统遗传学方法鉴定了该蛋白质,其中一组近交系小鼠被
研究了异丙肾上腺素治疗引起的心力衰竭特征。我们证明 GPNMB 表达
在梗死的小鼠心脏中增加一个数量级并调节心脏的伤口愈合事件
受伤后早期。我们发现,被招募到梗塞心脏的巨噬细胞是主要的
GPNMB 表达的来源。使用函数损失和增益方法,我们证明了 GPNMB
激活心脏成纤维细胞并诱导心肌细胞严重肥大。相比之下,基因缺失
GPNMB 可减弱梗死后心脏重塑,并与更好地保存心脏功能相关。
心脏功能。我们还提供的数据表明,人类血浆 GPNMB 水平与心脏密切相关
失败加强了 GPNMB 与梗死后心力衰竭发展之间的因果关系。
考虑到这些观察结果,我们假设 GPNMB 调节 (i) 梗塞后心脏重塑和
(ii) GPNMB 的抑制将减弱梗塞后心脏重塑。我们汇集了多学科
由心脏生理学、遗传学和细胞外基质生物学专业知识组成的团队来探究
GPNMB 在调节梗塞后心脏重塑中的作用和机制。在第一个目标中,我们将检查
GPNMB 在心脏重塑中的作用以及功能获得和丧失的方法。在第二个目标中,我们将
确定 GPNMB 激活机制并使用物理化学研究来确定受体
哪个 GPNMB 配体结合以及对结合至关重要的 GPNMB 结构域。在第三个目标中,我们将使用鼠标和
人类遗传学方法对受 GPNMB 影响的生物途径进行建模并询问常见问题
介导 GPNMB 对肌细胞和非肌细胞影响的下游信号通路。最后,我们将
确定 GPNMB 的药理学靶向是否可以作为减轻不良反应的治疗策略
心脏损伤后的重塑。
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:
$ 68.8万 - 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:
$ 68.8万 - 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:
$ 68.8万 - 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:
$ 68.8万 - 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:
$ 68.8万 - 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:
$ 68.8万 - 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:
$ 68.8万 - 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:
$ 68.8万 - 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:
$ 68.8万 - 项目类别:
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