Cardiomyocyte phenotype drives enhanced AMI recovery in spiny mice

项目摘要/摘要 大约每40秒就有一次心脏病发作(急性心肌梗死，AMI)。 这种损伤会导致心脏坏死，导致心律失常和心脏收缩能力降低，表现为 许多患者在首次急性心肌梗死后五年内发生心力衰竭(HF)。不幸的是，人类的心脏 受伤后不会再生，而且还没有得到批准的促进心脏修复的临床治疗方法。 此外，还没有建立再生哺乳动物模型来识别真正心脏的分子靶点。 修理。这项提案将通过研究具有非再生体的再生哺乳动物来解决这些局限性。 同时。 Acomys(非洲多刺小鼠)是一种与Mus(实验室小鼠)关系密切的哺乳动物。最近， 独立组织已经报道，Acomys能够在多个器官中再生受损组织。 最重要的是，在急性心肌梗死后，Acomys显示出显著的心脏保护作用，存活率高于 老鼠。我们的初步研究表明，Acomys能够挽救急性心肌梗死后的心功能。这 提案将进一步剖析在Acomys中看到的这些替代伤害反应的影响。 根据我们的初步结果，我建议探索在Acomys中看到的替代伤害反应。 我假设急性心肌梗死后Acomys患者心脏中的促再生细胞信号刺激成人心肌细胞 促进心肌细胞增殖，促进心肌恢复和存活。我将通过实现以下方法来验证这个假设 以下两个目标。目的1将研究心脏修复的程度和心肌细胞的作用 心脏病发作后Acomys的增殖与Mus的直接比较。我要检查一下心肌细胞 两种动物在急性心肌梗死后均有增殖。疤痕大小、功能恢复和血管生成也将被描述。 该提案的目标2将研究巨噬细胞来源的信号在Acomys心脏修复中的作用。自.以来 心肌细胞之间的细胞串扰在心脏内稳态和损伤后修复中都是重要的， 急性心肌梗死后心肌细胞的增殖可能受内在和外在信号的控制。巨噬细胞 在急性心肌梗死后早期大量渗入受损心脏，并已被证明影响心脏修复。我们的 初步数据表明，Acomys患者的巨噬细胞极化不同，具有更多的抗炎作用 巨噬细胞与小鼠比较。我假设Acomys的巨噬细胞释放细胞外信号 比小鼠巨噬细胞更能促进再生。为了验证我的假设，我将采用体内和体外两种方法。 巨噬细胞分泌体的浓缩技术及其对小鼠心脏修复的影响。这项提议将 建立Acomys作为研究缺血损伤后心脏恢复的新的哺乳动物模型。我期待着 这项研究的结果为心脏疾病新疗法的未来发展提供了蓝图 病人。

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.