Role of GPNMB in cardiac remodeling

项目总结/摘要 哺乳动物心脏在心肌梗死和死亡后再生心肌的能力很差 心肌被疤痕组织所取代。疤痕组织是非收缩性的，诱导不良的心脏重塑 并导致心腔扩张、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有助于 40%的新发心力衰竭病例。因此，迫切需要确定新的目标， 梗死后重塑和心力衰竭的发展。在本申请中，我们鉴定了GPNMB（糖蛋白 非转移性黑素瘤蛋白B）作为减弱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这种蛋白质，其中一组近交系小鼠被 研究了对异丙肾上腺素治疗的心力衰竭特征。我们证明GPNMB表达 在梗塞的鼠心脏中增加一个数量级，并调节心脏中的伤口愈合事件 受伤后早期。我们发现，巨噬细胞被招募到梗死的心脏是主要的 GPNMB表达的来源。使用损失和增益的功能的方法，我们表明，GPNMB 激活心脏成纤维细胞并诱导心肌细胞肥大。相反，基因缺失 GPNMB导致梗死后心脏重构的减弱，并与更好地保存心肌梗死相关。 心脏功能我们还提供了人体中GPNMB血浆水平与心脏病密切相关的数据。 失败加强了GPNMB和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）梗死后心脏重构， (ii)抑制GPNMB将减弱梗塞后心脏重塑。我们召集了一个多学科的 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团队， GPNMB在心肌梗死后心脏重构中的作用及机制在第一个目标中，我们将研究 GPNMB对心脏重构的作用与功能获得和丧失的方法。第二个目标，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， GPNMB配体结合的结构域和对结合至关重要的GPNMB结构域。在第三个目标中，我们将使用鼠标和 人类遗传学方法来模拟受GPNMB影响的生物途径，并询问常见的 下游信号通路介导GPNMB对肌细胞和非肌细胞的作用。最后我们将 确定GPNMB的药理学靶向是否可以是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.