Complement Activation and Initiation of Heart Regeneration

补体激活和心脏再生启动

• 批准号: 10116444
• 负责人: RICHARD T LEE
• 金额: $ 42.25万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116444
• 关键词: Acute; Adult; Ambystoma; Ambystoma mexicanum; American; Animals; Antibody Response; Antigens; Apical; Biological Models; Blinded; C5a anaphylatoxin receptor; Cardiac; Cardiac Myocytes; Cause of Death; Cell Cycle; Cells; Chick; Complement; Complement 5a; Complement Activation; Data; Embryo; Endothelial Cells; Enzyme Precursors; Event; Excision; Experimental Models; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Generations; Genes; Genetic; Genomics; Goals; Heart; Heart Injuries; Heart failure; Hour; Human; Image; Immune response; Impairment; Individual; Infarction; Inflammation; Injury; Innate Immune System; Investigation; Laboratories; Lead; Life; Limb structure; Liver; Mediating; Mexican; Molecular; Mus; Myocardial tissue; Myocardium; Natural regeneration; Organism; Pathway interactions; Peptides; Pharmacology; Play; Proteins; Randomized; Regenerative capacity; Regenerative response; Retina; Role; Salamander; Series; Signal Transduction; System; Systolic heart failure; Testing; Thrombin; Thrombosis; Tissues; Zebrafish; arm; cardiac regeneration; cell type; complement pathway; complement system; differential expression; experimental study; gene complementation; in vivo; injured; myocardial injury; neonatal mice; novel; receptor; regenerative; response; stable isotope; theories; tissue regeneration

The adult human heart fails to repopulate the myocardium with sufficient new cardiomyocytes following injury, and this limited capacity for regeneration can lead to systolic heart failure. In contrast, organisms from diverse taxa including adult salamanders and zebrafish have remarkable abilities to achieve complete regeneration of the myocardium following heart injury. We collaborated with multiple other laboratories to perform an unbiased genomic screen to identify genes that are differentially expressed during heart regeneration in three well-described model systems with enhanced regenerative capabilities: zebrafish, axolotl (Ambystoma mexicanum, or the Mexican salamander) and neonatal mice. We identified the gene for the complement 5a receptor, C5aR1, to be induced in the regenerating heart within the first 48 hours following injury in all of these species, and further showed that this increase in expression is primarily localized to cardiomyocytes and endothelial cells. C5aR1 is a G-protein coupled receptor that is one of the key receptors activated by the C5a peptide of the complement cascade. The complement pathway is an ancient and highly conserved immune response system that can activate inflammation and promote clearance of foreign and damaged materials. When the complement system is activated, a series of sequential cleavage and downstream activation steps occur, leading to amplification and eventually a common pathway activation of multiple G-protein coupled receptors, including C5aR1, the focus of this project. Here we show preliminary data demonstrating that inhibition of the C5aR1 receptor following cardiac injury impairs the cardiomyocyte cell cycle response to apical resection in axolotl as well as in the neonatal mouse, suggesting that complement activation and signaling could represent an evolutionarily conserved pathway in successful heart regeneration. As described in this proposal, this project aims to reveal the mechanism of how the activated complement pathway promotes heart regeneration. Our central theory is that the complement pathway plays an evolutionarily-conserved role in the heart regenerative response by orchestrating molecular signaling between acute injury and cardiomyocyte proliferation, a crucial component of heart regeneration. The project has three hypothesis-drive mechanistic aims, focusing on neonatal mice as the mammalian heart regeneration system. Understanding the early events in successful heart regeneration may allow us to intervene rationally to promote regeneration in the acutely injured adult human heart, such as in the first days after a sizable infarction.

成人心脏无法用足够的新心肌细胞重新填充心肌 损伤，而这种有限的再生能力可能导致收缩性心力衰竭。相反，生物体来自 包括成年蝾螈和斑马鱼在内的多种类群都具有实现完整目标的非凡能力 心脏损伤后心肌的再生。我们与多个其他实验室合作 进行无偏见的基因组筛选，以确定心脏过程中差异表达的基因 在三个具有增强再生能力的良好描述的模型系统中进行再生：斑马鱼、蝾螈 （Ambystoma mexicanum，或墨西哥蝾螈）和新生小鼠。我们确定了该基因 补体 5a 受体 C5aR1 在再生心脏后 48 小时内被诱导 所有这些物种的损伤，并进一步表明这种表达的增加主要集中于 心肌细胞和内皮细胞。 C5aR1 是一种 G 蛋白偶联受体，是关键受体之一 由补体级联的 C5a 肽激活。补体途径是一种古老且高度 保守的免疫反应系统，可以激活炎症并促进异物和异物的清除 损坏的材料。当补体系统被激活时，一系列连续的裂解和 发生下游激活步骤，导致扩增并最终激活 多个 G 蛋白偶联受体，包括本项目的重点 C5aR1。这里我们先展示一下初步的 数据表明，心脏损伤后抑制 C5aR1 受体会损害心肌细胞 蝾螈和新生小鼠对根尖切除的周期反应，表明补体 激活和信号传导可能代表成功心脏再生的进化保守途径。 正如该提案中所述，该项目旨在揭示激活的补体如何发挥作用的机制 途径促进心脏再生。我们的中心理论是补体途径起着 通过协调之间的分子信号在心脏再生反应中发挥进化保守的作用 急性损伤和心肌细胞增殖，这是心脏再生的重要组成部分。该项目共有三 假设驱动的机制目标，重点关注新生小鼠作为哺乳动物心脏再生系统。 了解成功心脏再生的早期事件可能使我们能够理性地干预 促进严重受伤的成年人心脏的再生，例如在相当大的心脏损伤后的最初几天 梗塞。