IL13 - A Novel Therapeutic Factor for Cardiac Regeneration

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。 截肢。尽管成年人和成年小鼠缺乏这种心脏再生反应，但有很大的作用 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 人类的过程，以更好地治疗心肌梗塞（MI）患者。细胞因子和生长因子 在很大程度上通过直接刺激在组织和器官再生的启动中发挥重要作用 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 IL13Rα1/IL4Rα 受体异二聚体。随后的体内研究表明 IL13 基因缺失会降低 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。 新生儿再生窗口。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 新生儿和成人中预先存在的 CM 和心脏再生的胞质分裂。目标 2 将调查 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 新生儿的心脏会痊愈，但成人的心脏却不会。总的来说，所提出的实验将确定细胞 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 成人缺乏这些机制。通过比较 CM 中的 IL13 依赖性机制和 免疫系统区分再生（新生儿）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。

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.