Cardiomyocyte phenotype drives enhanced AMI recovery in spiny mice

项目总结/摘要 大约每40秒就有一次心脏病发作（急性心肌梗死，AMI）。 这种损伤导致心脏坏死，导致心律失常和心脏收缩力降低， 许多患者在初次AMI后5年内出现心力衰竭（HF）进展。不幸的是，人类的心脏 损伤后不能再生，并且没有批准的临床治疗方法可以促进心脏修复。 此外，还没有建立再生哺乳动物模型来鉴定真正的心脏靶点。 修复.这项建议将通过研究再生哺乳动物与非再生动物来解决这些限制 同步 Acomys（非洲多刺小鼠）是一种与Mus（实验室小鼠）密切相关的哺乳动物。最近， 一些独立的研究小组报道说，Acomys能够使多个器官中的受损组织再生。 最重要的是，AMI后，Acomys表现出显著的心脏保护作用， 小鼠我们的初步研究表明Acomys能够挽救AMI后的心功能。这 该提案将进一步剖析Acomys中看到的这些替代伤害反应的效果。 基于我们的初步结果，我建议探索Acomys中观察到的替代损伤反应。 我假设AMI后Acomys心脏中的促再生细胞信号刺激成年心肌细胞 增殖并导致增强的心肌恢复和存活。我将通过实现 以下两个目标。目的1探讨心脏修复的程度及心肌细胞在其中的作用 Acomys在心脏病发作后的增殖与Mus直接比较。我将检查心肌细胞 AMI后两种动物的增殖。还将表征瘢痕大小、功能恢复和血管生成。 本提案的目的2将研究巨噬细胞源性信号对Acomys心脏修复的影响。以来 心脏细胞之间的细胞串扰在心脏稳态和损伤后修复中都是重要的， AMI后的心肌细胞增殖可能受内在和外在信号的控制。巨噬 在AMI后早期大量渗入受损心脏，并已显示影响心脏修复。我们 初步数据表明，Acomys中的巨噬细胞极化是不同的， 我假设Acomys巨噬细胞释放细胞外信号， 比小鼠巨噬细胞更有利于再生为了验证我的假设，我将在体内和体外 技术富集巨噬细胞分泌组，并检查其对小鼠心脏修复的作用。这项建议会 建立Acomys作为研究缺血性损伤后心脏恢复新的哺乳动物模型。我预计 本研究的结果为心脏病的新型心脏治疗的未来发展提供了蓝图。 患者

Project Summary/Abstract Approximately every 40 seconds, there is an incident of heart attack (acute myocardial infarction, AMI). This injury causes necrosis of heart leading to cardiac arrhythmia and reduced cardiac contractility, rendering progression of heart failure (HF) in many patients within five years of initial AMI. Unfortunately, the human heart does not regenerate after injury, and there is no approved clinical treatment that facilitates cardiac repair. Moreover, no regenerative mammalian models are established to identify molecular targets for bona fide cardiac repair. This proposal will address these limitations by studying regenerate mammal with a non-regenerator simultaneously. Acomys (African Spiny mice) is a mammal closely related to Mus (laboratory mouse). Recently, independent groups have reported that Acomys are capable of regenerating injured tissue in multiple organs. Most importantly, after AMI, Acomys demonstrated significant cardiac protection, with a higher survival rate than mice. Our preliminary studies revealed that Acomys is capable of rescuing cardiac function after AMI. This proposal will further dissect the effect of these alternative injury responses seen in Acomys. Based on our preliminary results, I proposed to explore the alternative injury response seen in Acomys. I hypothesized that pro-regenerative cellular signals in Acomys heart after AMI stimulate adult cardiomyocyte proliferation and result in enhanced myocardium recovery and survival. I will test this hypothesis by implementing the following two aims. Aim 1 will investigate the extent of cardiac repair and the role of cardiomyocyte proliferation in Acomys after a heart attack with direct comparison to Mus. I will examine cardiomyocyte proliferation in both species after AMI. Scar size, functional recovery and angiogenesis will also be characterized. Aim 2 of this proposal will investigate the effect of macrophage-derived signals on Acomys cardiac repair. Since cellular cross-talk between cardiac cells are important in both cardiac homeostasis and post-injury repair, cardiomyocyte proliferation after AMI is likely controlled by both intrinsic and extrinsic signals. Macrophages infiltrate the injured heart in abundance early after AMI, and have been shown to influence cardiac repair. Our preliminary data suggest that macrophage polarization in Acomys is different with more anti-inflammatory macrophages compared to Mus. I hypothesized that Acomys macrophage release extracellular signals that are more pro-regenerative than Mus macrophages. To test my hypothesis, I will employ both in vivo and in vitro techniques to enrich macrophage secretome and examine its effect on Mus cardiac repair. This proposal will establish Acomys as a novel mammalian model for studying cardiac recovery after ischemic injury. I anticipate the outcome of this study to provide a blueprint for the future development of novel cardiac therapies for cardiac patients.