Cardiomyocyte phenotype drives enhanced AMI recovery in spiny mice

心肌细胞表型促进多刺小鼠 AMI 恢复

• 批准号: 9911525
• 负责人: Hsuan Peng
• 金额: $ 0.83万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9911525
• 关键词: Acomys; Acute myocardial infarction; Address; Adult; African; Animals; Anti-Inflammatory Agents; Apoptotic; Arrhythmia; Biological Process; Biology; Bone Marrow; Cardiac; Cardiac Myocytes; Career Choice; Cell Proliferation; Cell Therapy; Cells; Cessation of life; Cicatrix; Clinical; Clinical Treatment; Cultured Cells; Data; Development; Echocardiography; Enzyme-Linked Immunosorbent Assay; Failure; Fellowship; Fibroblasts; Flow Cytometry; Future; Goals; Healthcare; Heart; Heart Injuries; Heart failure; High Prevalence; Homeostasis; Human; Immunization; Immunohistochemistry; In Vitro; Inflammatory; Injections; Injury; Knowledge; Label; Laboratory mice; Ligation; Mammals; Medicine; Methods; Modeling; Molecular; Molecular Target; Mononuclear; Morbidity - disease rate; Mus; Myocardial Infarction; Myocardial Ischemia; Myocardium; Natural regeneration; Necrosis; Neonatal; Organ; Outcome Study; Patients; Pattern; Peptides; Phenotype; Production; Recovery; Recovery of Function; Recurrence; Reperfusion Injury; Reporting; Research; Research Personnel; Role; Side; Signal Transduction; Study models; Survival Rate; Techniques; Testing; Tissues; Training; Translating; United States; Vision; Western Blotting; angiogenesis; base; cardiac repair; cardioprotection; clinical development; clinically relevant; comparative; cytokine; exosome; extracellular; extracellular vesicles; heart function; in vivo; injured; injury and repair; intravenous injection; ischemic injury; mRNA Expression; macrophage; mortality; mouse model; myocardial injury; nano; new therapeutic target; novel; novel therapeutic intervention; regenerative; repaired; response to injury; small molecule; treatment group

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.

项目摘要/摘要 大约每40秒，就会发生心脏病发作（急性心肌梗塞，AMI）。 这种损伤会导致心脏坏死导致心律不齐和心脏收缩性降低，并呈现 在初次AMI的五年内，许多患者的心力衰竭进展（HF）。不幸的是，人类的心 受伤后不会再生，也没有批准的临床治疗可促进心脏修复。 此外，没有建立再生哺乳动物模型来识别真正的心脏的分子靶标 维修。该提案将通过研究非再生剂来研究这些局限性 同时地。 Acomys（非洲棘小鼠）是与MUS（实验室小鼠）密切相关的哺乳动物。最近， 独立组报告说，Acomys能够在多个器官中再生受伤的组织。 最重要的是，在AMI之后，Acomys表现出明显的心脏保护，其存活率高于 老鼠。我们的初步研究表明，Acomys能够在AMI后挽救心脏功能。这 提案将进一步剖析ACOMY中看到的这些替代损伤反应的影响。 根据我们的初步结果，我建议探索ACOMYS中看到的替代损伤反应。 我假设AMI刺激成人心肌细胞后，Acomys心脏中的促增再生成细胞信号 增殖并导致心肌恢复和生存增强。我将通过实施来检验这一假设 以下两个目标。 AIM 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ACOMY的增殖，与MUS直接比较。我将检查心肌细胞 AMI后两种物种的增殖。疤痕大小，功能恢复和血管生成也将被表征。 该提案的目标2将研究巨噬细胞衍生的信号对ACOMYS心脏修复的影响。自从 心脏细胞之间的细胞串扰在心脏稳态和伤害后修复中都很重要， AMI后的心肌细胞增殖可能受到内在和外在信号的控制。巨噬细胞 AMI之后，早期浸润受伤的心脏，并已被证明会影响心脏修复。我们的 初步数据表明，Acomys中的巨噬细胞极化有所不同 与MUS相比，巨噬细胞。我假设Acomys巨噬细胞释放细胞外信号 比巨噬细胞更促进再生。为了检验我的假设，我将在体内和体外使用 富集巨噬细胞分泌的技术并检查其对MUS心脏修复的影响。该提议将 建立ACOMY作为一种新型哺乳动物模型，用于研究缺血性损伤后心脏恢复。我期待 这项研究的结果是为心脏疗法的未来发展提供蓝图 患者。