T-Cell-Mediated Inflammatory Response in Neonatal Heart Regeneration

新生儿心脏再生中 T 细胞介导的炎症反应

基本信息

批准号：
10625954
负责人：
ERIC N Olson
金额：
$ 41万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-05 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10625954
关键词：
Ablation Acute Adult Affect Anti-Inflammatory Agents Apoptosis Binding CCL24 gene Cardiac Cardiac Myocytes Cell Proliferation Cell secretion Cells Cytokine Receptors Development Dichloromethylene Diphosphonate Generations Genetic Growth Heart Helper-Inducer T-Lymphocyte Human Immune Immune response Immune signaling Immune system Impairment Inflammatory Inflammatory Response Injury Interleukin 4 Receptor Interleukin-4 Liposomes Macrophage Maps Mediating Mediator Mus Myocardial Infarction Natural Immunity Natural regeneration Neonatal Outcome Pathway interactions Phenotype Population Process Production Proliferating Receptor Signaling Regenerative capacity Regulation Role Signal Pathway Signal Transduction Surface T-Lymphocyte Testing Therapeutic Tissues adaptive immune response adaptive immunity angiogenesis cardiac regeneration cardiac repair cytokine gain of function immune activation in vivo injury recovery loss of function neonatal mice receptor recruit regeneration following injury repaired response to injury tool

项目摘要

Project Summary/Abstract The neonatal mouse heart possesses a remarkable ability to regenerate following injury and this cardiac regeneration is closely accompanied by robust activation of the immune system. Studies in the last decade have focused on the role of innate immunity during neonatal heart regeneration, and have established the necessary roles for macrophages in the repair and regeneration processes following myocardial infarction (MI). However, macrophages alone are not sufficient to drive neonatal regeneration, as neonatal mice lacking adaptive immunity but retaining innate immunity cannot regenerate. This result strongly suggests that other immune cells such as those involved in adaptive immunity also play a role in neonatal heart regeneration. In this project, we aim to explore the role of adaptive immunity, in particular the CD4+ T helper 2 (Th2) cell-mediated inflammatory response as a bridge between adaptive and innate immune signaling pathways that mediate neonatal cardiomyocyte (CM) proliferation in response to injury. Our preliminary results revealed that the Th2 cell secreted cytokine interleukin 4 (IL-4) is strongly upregulated in neonatal day 1 mouse hearts after MI and can promote CM proliferation. Its receptor IL-4ra is highly expressed in the proliferating CM population. We hypothesize that the Th2 cell-mediated IL-4 signaling promotes CM proliferation and macrophage transformation, as well as generating the cardiotropic factor CCL24 as a critical cytokine pathway in neonatal heart regeneration. Understanding how immune cells participate in neonatal heart regeneration will enlighten the development of potential therapeutics to promote adult heart repair and regeneration in humans.

项目概要/摘要新生小鼠心脏具有显着的损伤后再生能力，这种心脏再生与免疫系统的强劲激活密切相关。近十年的研究表明专注于先天免疫在新生儿心脏再生过程中的作用，并建立了必要的巨噬细胞在心肌梗死（MI）后修复和再生过程中的作用。然而，仅巨噬细胞不足以驱动新生小鼠再生，因为新生小鼠缺乏适应性免疫但保留先天免疫无法再生。这一结果强烈表明其他免疫细胞，例如那些参与适应性免疫的细胞也在新生儿心脏再生中发挥作用。在这个项目中，我们的目标是探索适应性免疫的作用，特别是 CD4+ T 辅助细胞 2 (Th2) 细胞介导的炎症反应作为介导新生儿的适应性和先天免疫信号通路之间的桥梁心肌细胞（CM）因损伤而增殖。我们的初步结果显示 Th2 细胞分泌细胞因子白细胞介素 4 (IL-4) 在 MI 后新生第 1 天小鼠心脏中强烈上调，并可促进 CM 增殖。其受体 IL-4ra 在增殖的 CM 群体中高度表达。我们假设 Th2 细胞介导的 IL-4 信号传导促进 CM 增殖和巨噬细胞转化，以及产生心肌因子 CCL24 作为新生儿心脏再生的关键细胞因子途径。了解免疫细胞如何参与新生儿心脏再生将启发心脏的发展促进人类成人心脏修复和再生的潜在疗法。