Molecular Mechanisms of Heart Regeneration

简介(申请人提供)：心脏病是美国和世界范围内导致残疾和死亡的主要原因之一。人的心脏在缺血损伤后不能通过瘢痕再生和愈合，从而逐渐导致心功能障碍。用新的心肌细胞和新生血管替代受损的心肌可能会恢复心功能。与哺乳动物相比，斑马鱼心脏具有显著的再生能力，手术切除后完全再生丢失的组织。斑马鱼心脏再生的分子和细胞机制知之甚少。在这个过程中，胚胎心外膜和周细胞/间充质标志物上调，表明心外膜被激活，并经历上皮到间充质的转变(EMT)以形成新的血管。我们发现，血小板衍生生长因子(PDGFs)对心脏再生很重要。在斑马鱼心脏再生过程中，阻断PDGF信号导致心肌细胞新生血管形成障碍和DNA合成减少。我们假设PDGF信号是心外膜细胞增殖、心外膜EMT和心肌细胞增殖所必需的。我们建议在体内(Aim 1)和体外(Aim 2)研究PDGFR2信号在心外膜细胞增殖、EMT和新血管形成中的作用。我们进一步建议确定PDGFR1信号在斑马鱼心肌细胞和心脏前体细胞中的功能(目标3)。我们独特的斑马鱼心脏再生模型和并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心脏疾病的新治疗方法。

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.