Molecular Mechanisms of Zebrafish Heart Regeneration

斑马鱼心脏再生的分子机制

• 批准号: 8078575
• 负责人: Ching-Ling E Lien
• 金额: $ 3.61万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8078575
• 关键词: Adult; Blood Vessels; Cardiac; Cardiac Myocytes; Cell Proliferation; Cells; Cicatrix; Coronary; Coronary Vessels; DNA biosynthesis; Defect; Degenerative Disorder; Development; Dominant-Negative Mutation; Embryo; Endothelial Cells; Epicardium; Excision; Failure; Fishes; Functional disorder; Future; Goals; Healed; Heart; Heart Diseases; Heat-Shock Response; Human; In Vitro; Injury; Lead; Mammals; Mediating; Mesenchymal; Modeling; Molecular; Myocardial; Myocardium; Natural regeneration; Operative Surgical Procedures; Organ; Organism; PDGFRA gene; PDGFRB gene; Pathology; Pericytes; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor Receptor; Process; Receptor Signaling; Regenerative Medicine; Research; Signal Transduction; System; Testing; Therapeutic; Time; Tissues; Transgenic Organisms; United States; Zebrafish; base; cell type; design; disability; epithelial to mesenchymal transition; healing; improved; in vivo; knock-down; mortality; neovascularization; novel therapeutic intervention; progenitor; promoter; public health relevance; regenerative; tissue regeneration

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.

描述（由申请人提供）：心脏病是美国和全球残疾和死亡率的主要原因之一。缺血性损伤后，人心无法通过疤痕再生和愈合，这逐渐导致心脏功能障碍。用新的心肌细胞和新血管造成损害的心肌替换可能恢复心脏功能。与哺乳动物相比，斑马鱼的心脏具有显着的再生能力，在手术切除后完全再生组织的再生。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，胚胎性心外膜和周环/间充质标记被上调，表明心外膜被激活，并经历上皮 - 间质转变（EMT）以形成新的血管。我们发现血小板衍生的生长因子（PDGF）对于心脏再生很重要。阻断PDGF信号导致斑马鱼心脏再生期间心肌细胞中新血管的形成受损和DNA合成降低。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PDGFR2信号传导在体内（AIM 1）和体外（AIM 2）中的心外膜细胞增殖，EMT和新血管形成的功能。我们进一步建议确定斑马鱼心肌细胞和心脏祖细胞中PDGFR1信号的功能（AIM 3）。我们独特的斑马鱼心脏再生模型以及体外和体内方法平行的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。我们的长期目标是将来开发新型心脏病治疗方法。 公共卫生相关性：再生医学对治疗先天性和退化性疾病有很大的希望。该提案的目的是确定斑马鱼（一种具有自然再生能力的生物体）心脏再生的分子和细胞机制。我们预计拟议的研究可能会导致发现，这些发现可能会增强未来患病人类心脏的再生能力。