Does Exercise Induce Cardiomyogenesis?

描述(由申请人提供)：传统观点认为成人心脏没有再生或心肌生成的能力已经受到质疑，现在有多条证据支持心脏再生的一些尽管有限的潜力。然而，在我们对调节这种再生能力的生理过程和途径的理解上存在着根本的差距。这一差距是一个重要的问题，因为它限制了我们利用心脏的再生能力在疾病中恢复心脏功能的能力。其长期目标是了解心脏再生的调节机制，并学习如何控制它。目前应用的目的是了解运动诱导心肌生成的机制和贡献。申请者实验室产生的初步数据表明，锻炼会在心脏中诱导潜在的再生反应。这些研究还发现了一条新的转录途径，包括共激活因子CITED4，作为心脏运动反应的关键介质。这一建议基于三个中心假设：1)运动增强心脏的内源性再生能力；2)CITED4对于运动诱导的心肌生成是必需的；3)依赖CITED4的心肌生成有助于在基线和疾病中运动的好处。这项建议的基本原理是，了解调节心脏内源性再生能力的生理机制将促进从治疗上利用这种能力来治疗与心肌细胞丧失相关的临床重要疾病。核心假设将在三个综合的具体目标中得到检验。在目标1中，一项最新开发的技术将被用于明确识别在两种运动模型中形成的新心肌细胞的数量、来源和命运。该技术结合了遗传命运图谱和基于质谱学的成像(多同位素成像质谱学)。在目标2中，将在基线和运动中确定心肌细胞和表达c-kit的心脏前体细胞中谱系特异性CITED4失活的后果。在目标3中，将检测运动诱导的心肌生成减轻心肌梗死后重构的能力，以及是否需要CITED4。体内研究将由分离的细胞群体支持，包括成人心肌细胞和表达c-kit的心脏前体细胞的体外研究，以阐明潜在的机制。该方法结合了创新的假设、技术和独特的动物模型，以及优秀合作研究团队的互补专业知识。这项拟议的研究意义重大，因为它有望促进我们对心脏再生和运动的好处以及它们减轻疾病的潜力的理解。这些研究将提供新的 对控制心脏生长和再生的生理机制的洞察，以及为心力衰竭和缺血性心脏病等与心肌细胞丧失相关的疾病的治疗方法提供信息。

DESCRIPTION (provided by applicant): The traditional view that the adult heart has no capacity for regeneration or cardiomyogenesis has been called into question, and multiple lines of evidence now support some albeit limited potential for cardiac regeneration. However, there is a fundamental gap in our understanding of the physiological processes and pathways that regulate this regenerative capacity. This gap represents an important problem because it limits our ability to exploit the heart's regenerative capacity to restore cardiac function in disease. Th long-term goal is to understand the mechanisms regulating cardiac regeneration and to learn how to control it. The objective of the current application is to understand the mechanisms and contribution of exercise-induced cardiomyogenesis. Preliminary data produced in the applicants' laboratories suggest that exercise induces a potentially regenerative response in the heart. These studies also identify a new transcriptional pathway, including the co-activator, CITED4, as a key mediator of the cardiac exercise response. This proposal is based on three central hypotheses: 1) that exercise enhances the endogenous regenerative capacity of the heart; 2) that CITED4 is necessary for exercise-induced cardiomyogenesis; and 3) that CITED4-dependent cardiomyogenesis contributes to the benefits of exercise at baseline and in disease. The rationale for the proposal is that understanding the physiological mechanisms regulating the heart's endogenous regenerative capacity will advance efforts to therapeutically harness this capacity for clinically important conditions associated with loss of cardiomyocytes. The central hypotheses will be tested in three integrated Specific Aims. In Aim 1, a recently developed technology that combines genetic fate mapping with mass spectrometry-based imaging (Multi-isotope Imaging Mass Spectrometry or MIMS) will be used to unambiguously identify the number, source, and fate of new cardiomyocytes formed in two models of exercise. In Aim 2, the consequences of lineage-specific CITED4 inactivation in cardiomyocytes and c-kit-expressing cardiac progenitor cells will be determined at baseline and in exercise. In Aim 3, the ability of exercise-induced cardiomyogenesis to mitigate remodeling after myocardial infarction and whether CITED4 is required will be examined. In vivo studies will be supported by in vitro investigation of isolated cell populations including adult cardiomyocytes and c-kit-expressing cardiac progenitor cells to elucidate the underlying mechanisms. The approach combines innovative hypotheses, technologies, and unique animal models with the complementary expertise of an outstanding team of collaborating investigators. The proposed research is significant, because it is expected to advance our understanding of cardiac regeneration and the benefits of exercise as well as their potential to mitigate disease. These studies will provide new insights into the physiological mechanisms controlling cardiac growth and regeneration as well as informing therapeutic approaches to diseases associated with cardiomyocyte loss such as heart failure and ischemic heart disease.