Young cardiomyocyte phenotype drives enhanced cardiac recovery in spiny mice

年轻心肌细胞表型促进多刺小鼠心脏恢复

• 批准号: 10250347
• 负责人: Hsuan Peng
• 金额: $ 4.6万
• 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: 2020-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10250347
• 关键词: Acomys; Address; Adult; African; Age; Aging; Animals; Automobile Driving; Calcium; Cardiac; Cardiac Myocytes; Cardiac health; Career Choice; Cell Therapy; Cellular Stress; Cicatrix; Clinical; Clinical Medicine; Diploidy; Elderly; Electrophysiology (science); Exhibits; Fellowship; Flow Cytometry; Frequencies; Future; Goals; Healthcare; Heart; Heart Diseases; Heart failure; Human; Immunohistochemistry; Injury; Knowledge; Laboratories; Laboratory mice; Longevity; Mammals; Methods; Modeling; Molecular; Molecular Target; Mononuclear; Morbidity - disease rate; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Natural regeneration; Neonatal; Organ; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patients; Phase; Phenotype; Physiologic pulse; Population; Publications; Reactive Oxygen Species; Recovery; Reporting; Research; Research Personnel; Risk Factors; Role; Side; Signal Transduction; Stress; Survival Rate; Testing; Tissues; Training; Translating; United States; Vertebrates; Work; age group; aged; aging population; angiogenesis; anti aging; cardiac repair; career; clinical development; clinically relevant; cost; design; functional decline; healing; heart function; in vivo; injured; injury recovery; insight; ischemic injury; mortality; mouse model; myocardial injury; neonatal mice; new therapeutic target; novel; novel therapeutic intervention; preservation; regeneration model; regenerative; regenerative biology; repaired; resilience; response; skills; small molecule

Aging is a major risk factor for ischemic heart disease, often caused by heart attack (myocardial infarction, MI). MI occurs at an alarmingly high rate in the United States (approximately one case every 40 seconds) and is the leading cause of morbidity and mortality in the geriatric population. At present, heart failure (HF) represents an unmet need with no approved clinical therapies to repair the damaged myocardium. As the population ages, the number of HF patients is projected to increase, doubling the annual cost by 2030. Identifying novel and translational mechanisms for robust cardiac repair presents a critical approach to counter aging-associated cardiac diseases and guide the design of future successful therapies. Acomys (African Spiny mouse) 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 MI, Acomys demonstrated significant cardiac protection, with a higher survival rate than mice. Our preliminary studies revealed that Acomys hearts retained a high frequency of young, proliferative phenotype cardiomyocytes (CM). This proposal will further dissect the mechanisms driving the youthful cardiac phenotype and cardiac protection in Acomys. The candidate will study Acomys and Mus side by side to test the central hypothesis that cytoprotective resilience to reactive oxygen species (ROS) preserves young phenotype CM into adulthood and drives enhanced myocardial preservation in Acomys after a heart attack. In the F99 phase of training, the candidate will continue investigating the contribution of Acomys cardiomyocytes in endogenous cardiac repair following MI in both young and aged animals. Specifically, the candidate will examine cardiomyocyte proliferation in both species and different age groups after MI. Scar size, cardiac function, and angiogenesis will also be characterized to determine the extent of recovery. In the K00 phase, the candidate will switch focus to identify molecular targets and pathways that allow Acomys to maintain a “young heart” into adulthood. The proposed work is designed to provide a robust transition training into aging research that will prepare the candidate for an academic career in translational anti-aging cardiac therapy. The proposed work will yield valuable information on endogenous cardiac repair in adult mammals. This knowledge will aid in the discovery of novel therapies and approaches for maintaining cardiac health throughout adulthood.

衰老是缺血性心脏病的主要危险因素，通常由心脏病发作（心肌梗死，MI）引起，在美国，MI 的发生率高得惊人（大约每 40 秒就有 1 例），并且是发病率和死亡率的主要原因。目前，心力衰竭（HF）是一种未满足的需求，没有批准的临床疗法来修复受损的心肌。随着人口老龄化，心力衰竭患者的数量预计将增加。到 2030 年，每年的费用将增加一倍。确定强健心脏修复的新颖转化机制，为对抗与衰老相关的心脏病提供了一种关键方法，并指导未来成功疗法的设计。Acomys（非洲刺鼠）是一种与衰老密切相关的哺乳动物。最近，独立研究小组报告称，Acomys 能够使多个器官的受损组织再生。最重要的是，在 MI 后，Acomys 表现出显着的心脏保护作用，且存活率高于小鼠。我们的初步研究表明，Acomys 心脏保留了高频率的年轻增殖表型心肌细胞 (CM)。该提案将进一步剖析 Acomys 年轻心脏表型和心脏保护的机制。候选者将同时研究 Acomys 和 Mus。测试中心假设，即细胞对活性氧 (ROS) 的保护能力将年轻的表型 CM 保留到成年，并在心脏病发作后促进 Acomys 心肌的保护增强。候选人将继续研究阿科米斯心肌细胞在年轻和老年动物心肌梗死后内源性心脏修复中的贡献，具体而言，候选人将检查心肌梗死后两个物种和不同年龄组的心肌细胞增殖、心脏功能和血管生成。在 K00 阶段，候选人将把重点转向确定使 Acomys 能够保持“年轻的心脏”进入成年期的分子目标和途径。衰老研究这将为候选人在转化抗衰老心脏治疗方面的学术生涯做好准备。拟议的工作将产生有关成年哺乳动物内源性心脏修复的宝贵信息，这些知识将有助于发现在整个成年期维持心脏健康的新疗法和方法。 。