IL13 - A Novel Therapeutic Factor for Cardiac Regeneration

项目摘要/摘要 斑马鱼和新生小鼠等生物能够在部分心脏再生后完全再生心脏。 截肢。尽管成年人类和成年小鼠缺乏这种心脏再生反应，但有很大的 对了解低等生物体如何发生心脏再生感兴趣，以便我们能够激活这些 在人类中更好地治疗心肌梗塞(MI)患者的过程。细胞因子与生长因子 在组织和器官再生的启动中起重要作用，在很大程度上是通过直接刺激 居留细胞的增殖，或通过伤口愈合炎症细胞的募集和激活。第二类 细胞因子白介素13(IL13)激活两者的促增殖信号分子(如AKT和ERK1/2) 新生儿和成人CMS通过信号途径刺激心肌细胞周期活动 IL13Rα1/IL4Rα受体异源二聚体。随后的体内研究表明，IL13基因缺失减少 CM细胞周期活性和大量M2样免疫细胞，并抑制新生儿心脏再生， 而重组IL-13能促进CM细胞周期活性，延长 新生儿再生窗。在这里，我们建议确定IL13促进的细胞机制 在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。 目的1验证白介素13通过白介素13Rα1/白介素4Rα受体直接在不育系上传递信号促进 新生儿和成人原有CMS的胞质分裂和心脏再生。目标2将调查 新生儿和成人心肌梗塞后IL13的细胞来源，并将检验IL13促进的假说 IL-13R-α-1/IL-4R-α信号介导的组织驻留巨噬细胞极化及其促进心肌梗死后的作用 治愈的是新生儿，而不是成年人的心脏。总的来说，拟议中的实验将确定细胞 新生儿再生过程中IL13信号的类型特异性介质，并将评估保存情况，或 在成人中，这些机制缺失。通过比较CMS和CMS中IL13依赖的机制 区分再生(新生)和非再生(成年)小鼠心脏的免疫系统，我们 目的确定增强成人心脏再生能力的可行途径。

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.