Complement Activation and Initiation of Heart Regeneration

补体激活和心脏再生启动

基本信息

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
项目类别：
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

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

展开

项目摘要

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.

成人人的心脏无法用足够的新心肌细胞重新填充心肌受伤，这种有限的再生能力会导致收缩性心力衰竭。相反，有机体来自包括成人sal和斑马鱼在内的各种分类单元具有非凡的能力心脏损伤后心肌的再生。我们与其他多个实验室合作执行公正的基因组筛选，以识别在心脏中差异表达的基因具有增强能力的三个良好描述的模型系统的再生：斑马鱼，Axolotl （墨西哥ambystoma，或墨西哥sal）和新生儿小鼠。我们确定了补体5A受体C5AR1，在后的最初48小时内诱导在再生心脏中诱导所有这些物种的伤害，进一步表明表达的增加主要定位于心肌细胞和内皮细胞。 C5AR1是G蛋白偶联受体，是关键受体之一由补体级联的C5A肽激活。补体途径是一个古老而高度的保守的免疫反应系统，可以激活炎症并促进外国的清除材料受损。当激活补体系统时，一系列顺序裂解和发生下游激活步骤，导致放大，最终导致了一个常见的途径激活多种G蛋白耦合受体，包括C5AR1，是该项目的重点。在这里我们展示初步数据表明，心脏损伤后对C5AR1受体的抑制会损害心肌细胞细胞对Axolotl以及新生小鼠中顶端切除的循环反应，表明补体激活和信号传导可以代表成功心脏再生中进化保守的途径。如本提案中所述，该项目旨在揭示如何激活补体的机制途径促进心脏再生。我们的中心理论是补体途径发挥通过在心脏再生反应中的进化作用，通过策划分子信号传导急性损伤和心肌细胞增殖，这是心脏再生的关键组成部分。该项目有三个假设 - 驱动机械的目的是将新生儿小鼠作为哺乳动物心脏再生系统。了解成功心脏再生中的早期事件可能使我们能够合理介入促进急性受伤的成年人心脏的再生，例如在大量之后的第一天梗塞。