Young cardiomyocyte phenotype drives enhanced cardiac recovery in spiny mice

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)引起。在美国，心肌梗死的发病率高得惊人(大约每40秒就有一例)，是老年人口发病率和死亡率的主要原因。目前，心力衰竭(HF)是一种尚未得到满足的需求，没有批准的临床治疗方法来修复受损的心肌。随着人口老龄化，预计心力衰竭患者的数量将增加，到2030年，每年的费用将翻一番。识别新的和翻译的强大的心脏修复机制是对抗衰老相关心脏疾病和指导未来成功治疗的设计的关键途径。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，独立组织报道称，Acomys能够在多个器官中再生受损组织。最重要的是，心肌梗死后，Acomys表现出显著的心脏保护作用，存活率高于小鼠。我们的初步研究表明，Acomys的心脏保留了高比例的年轻、增殖表型心肌细胞(CM)。这项建议将进一步剖析驱动Acomys年轻心脏表型和心脏保护的机制。候选人将同时研究Acomys和Mus，以测试中心假设，即对活性氧簇(ROS)的细胞保护弹性将年轻的表型CM保留到成年，并推动Acomys在心脏病发作后加强心肌保护。在F99训练阶段，候选人将继续研究Acomys心肌细胞在幼年和老年动物心肌梗死后内源性心脏修复中的作用。具体地说，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情况。疤痕的大小、心功能和血管生成也将被用来确定恢复的程度。在K00阶段，候选人将把重点转向识别分子靶标和途径，使Acomys在成年后保持一颗“年轻的心脏”。拟议的工作旨在提供向衰老研究的强有力的过渡培训，为候选人在翻译性抗衰老心脏治疗方面的学术生涯做好准备。这项拟议的工作将为成年哺乳动物的内源性心脏修复提供有价值的信息。这一知识将有助于发现新的治疗方法和方法，以保持整个成年期的心脏健康。

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.