Molecular Mechanisms of Zebrafish Heart Regeneration

描述（由申请人提供）：心脏病是美国和全球残疾和死亡的主要原因之一。缺血性损伤后，人的心脏不能再生和愈合的疤痕，这逐渐导致心功能障碍。用新的心肌细胞和新血管化代替受损的心肌可以恢复心脏功能。与哺乳动物相比，斑马鱼的心脏具有非凡的再生能力，可以在手术切除后完全再生失去的组织。关于斑马鱼心脏再生的分子和细胞机制知之甚少。在此过程中，胚胎心外膜和周细胞/间充质标记物上调，表明心外膜被激活并经历上皮细胞向间充质细胞转化（EMT）以形成新血管。我们发现血小板衍生生长因子（PDGF）对心脏再生很重要。阻断PDGF信号传导导致斑马鱼心脏再生过程中心肌细胞新血管形成受损和DNA合成减少。我们假设PDGF信号传导是心外膜细胞增殖、心外膜EMT和心肌细胞增殖所必需的。我们建议表征PDGFR 2信号传导在体内（Aim 1）和体外（Aim 2）心外膜细胞增殖、EMT和新血管形成中的功能。我们进一步提出确定PDGFR 1信号转导在斑马鱼心肌细胞和心脏祖细胞中的功能（目的3）。我们独特的斑马鱼心脏再生模型和平行的体外和体内方法将使我们能够确定斑马鱼心脏再生的分子和细胞机制。我们的长期目标是在未来开发新的心脏病治疗方法。 公共卫生相关性：再生医学在治疗先天性和退行性疾病方面有很大的前景。这项计划的目的是确定斑马鱼心脏再生的分子和细胞机制，斑马鱼是一种具有天然再生能力的生物体。我们希望这项拟议中的研究可以导致未来可能增强患病人类心脏再生能力的发现。

DESCRIPTION (provided by applicant): Heart disease is among the leading causes of disability and mortality in United States and worldwide. After ischemic injury, human hearts cannot regenerate and heal by scarring, which gradually leads to cardiac dysfunction. Replacing the damaged myocardium with new cardiomyocytes and neovascularization may restore cardiac function. By contrast to mammals, zebrafish hearts have remarkable regenerative capacity, completely regenerating lost tissue after surgical resection. Very little is known about the molecular and cellular mechanisms of heart regeneration in zebrafish. During this process, embryonic epicardial and pericyte/mesenchymal markers are upregulated, suggesting that the epicardium is activated and undergoes an epithelial-to-mesenchymal transition (EMT) to form new blood vessels. We found platelet-derived growth factors (PDGFs) are important for heart regeneration. Blocking PDGF signaling caused impaired new blood vessel formation and decreased DNA synthesis in cardiomyocytes during zebrafish heart regeneration. We hypothesize that PDGF signaling is required for epicardial cell proliferation, epicardial EMT, and cardiomyocyte proliferation. We propose to characterize the functions of PDGFR2 signaling in epicardial cell proliferation, EMT, and new blood vessel formation in vivo (Aim 1) and in vitro (Aim 2). We further propose to determine the function of PDGFR1 signaling in zebrafish cardiomyocytes and cardiac progenitors (Aim 3). Our unique zebrafish heart regeneration model and parallel in vitro and in vivo approaches will allow us to determine the molecular and cellular mechanisms of zebrafish heart regeneration. Our long-term goal is the development of novel therapeutic approaches for heart diseases in the future. PUBLIC HEALTH RELEVANCE: Regenerative medicine holds a great deal of promise for treating congenital and degenerative diseases. The goal of this proposal is to determine the molecular and cellular mechanisms of heart regeneration in zebrafish, an organism with a natural regenerative ability. We expect the proposed research can lead to findings that may enhance regenerative capacity in diseased human hearts in the future.