IL13 - A Novel Therapeutic Factor for Cardiac Regeneration

IL13 - 心脏再生的新型治疗因子

基本信息

批准号：
10846960
负责人：
Caitlin C O'Meara
金额：
$ 6.21万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
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：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10846960
关键词：
Address Adult Amputation Apical Cardiac Myocytes Cell Cycle Cells Chronic Complement Cre driver Cytokinesis Data Development Excision Future Genetic Goals Growth Factor Heart Heart failure Human IL-13Ralpha1 Immune Immune response Immune system In Vitro Infarction Inflammatory Injury Interleukin-13 Knock-out Knockout Mice Long-Term Effects Lower Organism LoxP-flanked allele Lung MAPK3 gene Macrophage Maps Mediator Mus Myoblasts Myocardial Myocardial Infarction Natural regeneration Neonatal Organism Pathway interactions Patients Play Population Process Proliferating Proliferation Marker Proteins Proto-Oncogene Proteins c-akt Publishing Rattus Recombinant Interleukin-13 Regenerative capacity Regenerative response Reporter Reporting Research Role Signal Transduction Signaling Molecule Skeletal Muscle Smooth Muscle Myocytes Source Testing Tissues Transgenes Vertebrates Weather Work Zebrafish cardiac regeneration cardiac repair cardioprotection cell type cytokine experimental study functional improvement healing improved in vivo interest interleukin-13 receptor model organism monocyte neonatal injury neonatal mice neonate novel novel therapeutics organ regeneration preservation programs protective factors receptor recruit regeneration following injury regeneration model regeneration potential regenerative regenerative treatment tissue regeneration wound healing

项目摘要

PROJECT SUMMARY/ABSTRACT Organisms such as zebrafish and neonatal mice are capable of complete heart regeneration following partial amputation. Although adult humans and adult mice lack this cardiac regeneration response, there is great interest in understanding how heart regeneration can occur in lower organisms so that we can activate these processes in humans to better treat patients following myocardial infarction (MI). Cytokines and growth factors play a significant role in the initiation of tissue and organ regeneration in large part by directly stimulating proliferation of resident cells, or by recruitment and activation of wound healing inflammatory cells. The type II cytokine Interleukin 13 (IL13) activates pro-proliferative signaling molecules (e.g. AKT and ERK1/2) in both neonatal and adult CMs and stimulates cardiac myocyte cell cycle activity via signaling through the IL13Rα1/IL4Rα receptor heterodimer. Subsequent in vivo studies show that IL13 genetic deletion decreases CM cell cycle activity and abundance of M2-like immune cells, and inhibits heart regeneration in neonates, while administration of recombinant IL13 is capable of promoting CM cell cycle activity and extending the neonatal regenerative window. Here, we propose to identify the cellular mechanisms by which IL13 promotes heart regeneration post MI in neonatal mice and test the extent in which these mechanisms exist in the adult. Aim 1 tests the hypothesis that IL13 signals directly on CMs via the IL13Rα1/IL4Rα receptor to promote cytokinesis of pre-existing CMs and heart regenerating in the neonate and adult. Aim 2 will investigate the cellular source of IL13 following MI at neonatal and adult stages and will test the hypothesis that IL13 promotes tissue resident macrophage polarization via IL13Rα1/IL4Rα signaling and these macrophages facilitate post MI healing in the neonatal, but not the adult heart. Collectively, the proposed experiments will determine the cell type specific mediators of IL13 signaling during neonatal regeneration and will assess the preservation, or absence, of these mechanisms in the adult. By comparing the IL13-depentent mechanisms in CMs and the immune system that differentiate the regenerative (neonatal) and non-regenerative (adult) mouse heart, we aim to identify actionable pathways for augmenting regenerative capacity in the adult heart.

项目概要/摘要斑马鱼和新生小鼠等生物体能够在部分心脏再生后完全再生。尽管成年人和成年小鼠缺乏这种心脏再生反应，但存在很大的作用。有兴趣了解低等生物体中如何发生心脏再生，以便我们可以激活这些细胞因子和生长因子在人类中更好地治疗心肌梗死（MI）患者。在很大程度上通过直接刺激在启动组织和器官再生中发挥重要作用常驻细胞的增殖，或通过伤口愈合炎症细胞的募集和激活 II 型。细胞因子白细胞介素 13 (IL13) 激活促增殖信号分子（例如 AKT 和 ERK1/2）新生儿和成人 CM 并通过信号传导刺激心肌细胞细胞周期活动随后的体内研究表明IL13Rα1/IL4Rα受体异二聚体减少。 CM 细胞周期活性和 M2 样免疫细胞丰度，并抑制新生儿心脏再生，而重组IL13的施用能够促进CM细胞周期活性并延长细胞周期。在这里，我们建议确定 IL13 促进的细胞机制。新生小鼠心肌梗死后心脏再生，并测试这些机制在成年小鼠中存在的程度。目标 1 检验以下假设：IL13 通过 IL13Rα1/IL4Rα 受体直接在 CM 上发出信号，以促进目标 2 将研究新生儿和成人中已有 CM 的胞质分裂和心脏再生。新生儿和成人阶段 MI 后 IL13 的细胞来源，并将检验 IL13 促进的假设通过 IL13Rα1/IL4Rα 信号传导的组织驻留巨噬细胞极化，这些巨噬细胞促进 MI 后总的来说，拟议的实验将确定新生儿心脏的愈合情况，而不是成人心脏的愈合情况。新生儿再生过程中 IL13 信号传导的类型特异性介质，并将评估保存情况，或通过比较 CM 和 CM 中的 IL13 依赖性机制，发现成人中缺乏这些机制。免疫系统区分再生（新生）和非再生（成年）小鼠心脏，我们旨在确定增强成人心脏再生能力的可行途径。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Global IL4Rα blockade exacerbates heart failure after an ischemic event in mice and humans.

在小鼠和人类的缺血事件后，全局 IL4Rα 阻断会加剧心力衰竭。

DOI：
发表时间：
2024-05-01
期刊：
影响因子：
0
作者：
Alvarez;Almeida, Victor A;Knas, Makenna C;Buday, Sydney L;Patterson, Michaela;O'Meara, Caitlin C
通讯作者：
O'Meara, Caitlin C

Interleukin-13 and its receptor are synaptic proteins involved in plasticity and neuroprotection.

Interleukin-13 及其受体是参与可塑性和神经保护的突触蛋白。

DOI：
发表时间：
2023-01-13
期刊：
影响因子：
16.6
作者：
Li, Shun;Olde Heuvel, Florian;Rehman, Rida;Aousji, Oumayma;Froehlich, Albrecht;Li, Zhenghui;Jark, Rebecca;Zhang, Wanhong;Conquest, Alison;Woelfle, Sarah;Schoen, Michael;O Meara, Caitlin C;Reinhardt, Richard Lee;Voehringer, David;Kassubek, Ja
通讯作者：
Kassubek, Ja

Upstream regulation of the Hippo-Yap pathway in cardiomyocyte regeneration.

Hippo-Yap 通路在心肌细胞再生中的上游调控。