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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

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.

成人心脏不能用足够的新心肌细胞重新填充心肌