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：
Arjun Deb
金额：
$ 68.8万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
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：
https://reporter.nih.gov/project-details/10521279
关键词：
Acute myocardial infarction Adopted Affect Antisense Oligonucleotides Attenuated Binding Biological Biological Markers Biological Models Biology Bone Marrow Transplantation Cardiac Cardiac Myocytes Cardiovascular Agents Cells Cicatrix Circulation Collaborations Data Dependovirus Development Diagnosis Dilatation - action Event Extracellular Domain Extracellular Matrix Fibroblasts Fibrosis GPR39 gene Genes Genetic Glycoproteins Heart Heart Hypertrophy Heart Injuries Heart failure Heparitin Sulfate Human Human Genetics Hypertrophy Inbred Strains Mice Infarction Injury Integral Membrane Protein Isoproterenol Ligand Binding Macrophage Maps Mediating Mitochondria Mus Muscle Cells Myocardial Infarction Myocardium Natural regeneration Nonmetastatic Orphan Pathway interactions Peptide Hydrolases Pharmacologic Substance Physiological Physiology Plasma Proteins Proteomics Public Health Role Signal Pathway Site-Directed Mutagenesis Source System Therapeutic Time Tissues Wild Type Mouse attenuation experimental study gain of function genetic approach healing heart function heart preservation hemodynamics in vivo insight loss of function melanoma mouse genetics mouse model multidisciplinary novel pharmacologic pressure protein B receptor recruit repaired response trait wound 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。尽管心血管药物的最佳使用，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 表达在梗塞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) 梗死后心脏重塑和 (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 在调节梗死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。