IL13 - A Novel Therapeutic Factor for Cardiac Regeneration

项目概要/摘要 生物体如斑马鱼和新生小鼠能够在部分心脏再生后完全再生。 截肢虽然成年人和成年小鼠缺乏这种心脏再生反应，但有很大的 有兴趣了解心脏再生如何在低等生物中发生， 在人类中的过程，以更好地治疗心肌梗死（MI）后的患者。细胞因子和生长因子 在组织和器官再生的启动中起重要作用， 驻留细胞的增殖，或通过伤口愈合炎性细胞的募集和活化。II型 细胞因子白细胞介素13（IL 13）激活促增殖信号分子（例如AKT和ERK 1/2）， 新生儿和成人CM和刺激心肌细胞的细胞周期活动，通过信号通过 IL 13 R α1/IL 4 R α受体异源二聚体。随后的体内研究表明，IL 13基因缺失降低了 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， 而施用重组IL 13能够促进CM细胞周期活性并延长CM细胞周期。 新生儿再生窗在这里，我们建议确定IL 13促进的细胞机制， 新生小鼠心肌梗死后的心脏再生，并测试这些机制在成年小鼠中存在的程度。 目的1验证IL 13通过IL 13 R α1/IL 4 R α受体直接在CM上信号传导以促进细胞增殖的假设。 既存CM的胞质分裂以及新生儿和成人的心脏再生。目标2将调查 在新生儿和成人阶段MI后IL 13的细胞来源，并将测试IL 13促进MI的假设。 组织驻留巨噬细胞通过IL 13 R α1/IL 4 R α信号转导极化，这些巨噬细胞促进MI后 新生儿的心脏可以愈合但成人的心脏不行总的来说，拟议的实验将确定细胞 新生儿再生期间IL 13信号传导的类型特异性介质，并将评估保存，或 成年人缺乏这些机制。通过比较CMs中IL 13依赖性机制和 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。

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.