Role of GPNMB in cardiac remodeling

项目摘要/摘要 哺乳动物的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。疤痕组织是非收缩的，会导致不利的心脏重构 并导致心腔扩张、心肌细胞肥大和心力衰竭的发展。 尽管最佳使用心血管药物，但心肌梗死后的不良重塑有助于 占所有新发心力衰竭病例的40%。因此，迫切需要确定新的衰减目标 心肌梗死后重构与心力衰竭的发展。在本申请中，我们鉴定了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构的新靶点。我们 使用系统遗传学方法鉴定了这种蛋白质，在这种方法中，一组近亲交配的小鼠品系被 研究了异丙肾上腺素治疗对心力衰竭特征的影响。我们证明了GPNMB表达式 梗死小鼠心脏增加一个数量级并调节心脏创伤愈合事件 受伤后早期。我们发现，被募集到梗塞心脏的巨噬细胞是主要的 GPNMB表达式的源。利用函数损失和函数增益的方法，我们证明了GPNMB 激活心脏成纤维细胞，诱导心肌细胞深度肥大。相比之下，基因缺失 GPNMB可减轻心肌梗死后的重构，并与更好地保存 心脏功能。我们还提供了人类血浆中GPNMB水平与心脏密切相关的数据 失败强化了GPNMB与梗死后心力衰竭的发展之间的因果关系。 考虑到这些观察，我们假设GPNMB调节(I)梗死后心脏重塑和 (Ii)抑制GPNMB可减轻心肌梗死后的心脏重构。我们已经组建了一个多学科的 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小组审问 GPNMB在调节心肌梗死后心脏重构中的作用及机制在第一个目标中，我们将检查 GPNMB在心脏重构中的作用与功能的获得和丧失途径。在第二个目标中，我们将 确定GPNMB激活的机制，并使用物理化学研究来确定受体以 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 人类遗传学方法模拟受GPNMB影响的生物通路并询问共同 介导GPNMB对心肌细胞和非心肌细胞影响的下游信号通路。最后，我们会 确定GPNMB的药理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。

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.