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Investigating the role of the complement system in cardiac regeneration

研究补体系统在心脏再生中的作用

基本信息

批准号：
10093224
负责人：
Niranjana Natarajan
金额：
$ 6.74万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10093224
关键词：
Acute Address Adult Agonist Ambystoma Animal Model Apical Birth C5a anaphylatoxin receptor Cardiac Cardiac Myocytes Cell Proliferation Cell division Cicatrix Complement Complement 3a Complement 5a Complement Activation Complement Receptor Complement component C5 Data Dominant-Negative Mutation Embryo Endothelial Cells Event Excision Exhibits Fibrosis G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Gene Transfer Genes Genetic Heart Heart Diseases Heart Injuries Heart failure Hour IL6 gene Immune response Impairment Inflammatory Inflammatory Response Injury Innate Immune System Knockout Mice Laboratories Lead Life Limb structure Liver Lymphoid Cell Mammals Mediating Modeling Molecular Mouse Cell Line Mus Myocardial Infarction Myocardium Natural regeneration Neonatal Newts Pathway interactions Peptides Pharmacology Receptor Signaling Reperfusion Injury Resources Retina Role Signal Transduction Testing Thrombin Tissues United States Up-Regulation Zebrafish cardiac regeneration complement system deep sequencing experimental study immune system function mortality mouse model receptor receptor expression receptor function regenerative repaired response tool transcriptome sequencing transcriptomics

项目摘要

Project summary: The mammalian heart has a limited regenerative potential due to the low proliferation rate of adult cardiomyocytes. However, a narrow regenerative window has been identified in the neonatal murine heart, wherein mice are able to successfully regenerate their hearts both at the tissue and functional level following injury. In a cross-species transcriptomic screen in the Lee laboratory, inflammatory response genes including complement receptors were upregulated in a conserved manner in the regenerating heart of three model organisms – axolotl, mouse and zebrafish. The most-upregulated inflammatory response genes include G-protein coupled receptors (GPCR) for complement components, complement 5a receptor (C5aR1) and complement 3a receptor (C3aR). The complement system is part of the innate immune system and functions to clear foreign material. Activation of an early immune response is a shared feature observed in the regenerating heart of model organisms, consistent with the upregulation of C5aR1 and C3aR observed. C5aR1 is a GPCR that functions as a complement receptor for C5a, generated by proteolytic cleavage of complement component 5. Pharmacologic inhibition of C5aR1 after apical resection results in an impaired cardiomyocyte proliferative response in all three model organisms studied – axolotl, mouse and zebrafish. I propose to investigate the role of complement activation in murine cardiac regeneration, to elucidate the molecular mechanisms that initiate effective repair and cardiomyocyte proliferation in the mammalian heart following injury. To understand the role of C5aR1, I will utilize global genetic deletion mouse model of C5aR1 to assess cardiac regeneration after apical resection at the cellular, tissue and functional level in C5aR1 wild-type and C5aR1 knock-out mice. I propose to assess cardiomyocyte proliferation in C5aR1 wild-type and knock-out mice to understand the sequence of molecular events in the injured heart that initiate cardiomyocyte proliferation and effective regeneration. Furthermore, I will investigate the role of C3aR in early cardiac regeneration using pharmacologic inhibition and C3aR knock-out mice. In addition, I will perform experiments in non-regenerative murine models (7- day-old mice) to investigate if acute activation of complement signaling (C3 and C5) will increase cardiomyocyte proliferation following injury. These studies will likely define a mechanistic pathway of early events critical for the initiation of cardiomyocyte proliferation in the myocardium.

项目概要：哺乳动物的心脏由于成体的低增殖率而具有有限的再生潜力。心肌细胞然而，在新生小鼠心脏中已经确定了狭窄的再生窗口，其中小鼠能够在组织和功能水平上成功地再生它们的心脏，受伤后。在李实验室的跨物种转录组筛选中，炎症反应包括补体受体在内的基因在再生心脏中以保守的方式上调，三种模式生物-蝾螈，小鼠和斑马鱼。炎症反应的最高水平基因包括补体成分的G蛋白偶联受体（GPCR）、补体5a受体（C5 aR 1）和补体3a受体（C3 aR）。补体系统是先天免疫系统的一部分，清除异物的系统和功能。早期免疫反应的激活是一个共同的特征在模型生物体的再生心脏中观察到，与C5 aR 1的上调一致，观察到C3 aR。C5 aR 1是一种GPCR，作为C5 a的补体受体发挥作用，由C5 a产生，补体成分5的蛋白水解裂解。根尖切除术后C5 aR 1的药理学抑制导致所研究的所有三种模式生物体中心肌细胞增殖反应受损-蝾螈，老鼠和斑马鱼。我建议研究补体激活在小鼠心脏中的作用，再生，以阐明启动有效修复和心肌细胞的分子机制，损伤后哺乳动物心脏的增殖。为了理解C5 aR 1的作用，我将利用全球 C5 aR 1基因缺失小鼠模型，以评估在细胞处进行心尖切除后的心脏再生，在C5 aR 1野生型和C5 aR 1敲除小鼠中的组织和功能水平。我建议评估 C5 aR 1野生型和敲除小鼠的心肌细胞增殖，以了解损伤心脏中启动心肌细胞增殖和有效再生的分子事件。此外，我将研究C3 aR在早期心脏再生中的作用，和C3 aR敲除小鼠。此外，我将在非再生小鼠模型中进行实验（7- 10）。日龄小鼠）以研究补体信号传导（C3和C5）的急性活化是否会增加损伤后心肌细胞增殖。这些研究可能会定义一个机制的途径，对心肌中心肌细胞增殖的起始至关重要的事件。