Does Exercise Induce Cardiomyogenesis?

运动会诱导心肌生成吗？

基本信息

批准号：
8699591
负责人：
ANTHONY ROSENZWEIG
金额：
$ 44.86万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-25 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8699591
关键词：
Adult Animal Model Animals CCAAT-Enhancer-Binding Proteins Cardiac Cardiac Myocytes Cardiovascular system Cells Chronic Clinical Research Cues Data Disease Exercise Genetic Goals Growth Health Heart Heart failure Human Image Imaging technology In Vitro Infarction Injury Investigation Isotopes Knockout Mice Knowledge Label Laboratories Lead Learning Maps Mass Spectrum Analysis Mediator of activation protein Mission Modeling Mus Myocardial Infarction Myocardial Ischemia Natural regeneration Pathway interactions Physiological Physiological Processes Population Process Proliferation Marker Proto-Oncogene Protein c-kit Public Health Research Research Personnel Role Source Stem cells Structure Technology Testing Therapeutic Thymidine Ventricular Remodeling Work base cardiac regeneration in vivo innovation insight new technology novel therapeutic intervention overexpression public health relevance regenerative repaired response

项目摘要

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.

描述（由申请人提供）：传统观点，即成年心脏没有再生或心脏病的能力已受到质疑，现在多种证据支持了某些有限的心脏再生潜力。但是，我们对调节这种再生能力的生理过程和途径的理解存在根本差距。这一差距代表了一个重要的问题，因为它限制了我们利用心脏再生能力恢复疾病中心脏功能的能力。长期目标是了解调节心脏再生的机制并学习如何控制它。当前应用的目的是了解运动诱导的心肌生成的机制和贡献。申请人实验室中产生的初步数据表明，运动在心脏中引起潜在的再生反应。这些研究还确定了一种新的转录途径，包括共激活因子引用4，作为心脏运动反应的关键介体。该提议基于三个中心假设：1）运动增强了心脏的内源性再生能力； 2）引用4是运动诱导的心肌生成所必需的； 3）引用4依赖性的心肌生成有助于基线和疾病的运动益处。该提案的理由是，了解调节心脏内源性再生能力的生理机制将促进治疗能力利用与心肌细胞丧失有关的临床重要疾病的能力。中心假设将以三个集成的特定目的进行测试。在AIM 1中，将遗传命运映射与质谱基于质谱的成像（多同位素成像质谱法或MIMS）相结合的技术将明确识别在两种运动模型中形成的新心肌细胞的数量，源和命运。在AIM 2中，将在基线和运动中确定心肌细胞和表达C-KIT表达心脏祖细胞的谱系特异性引用4失活的后果。在AIM 3中，将检查运动诱导的心肌生成缓解心肌梗塞后的重塑以及是否需要引用4的能力。体内研究将通过在体外研究（包括成年心肌细胞和表达C-KIT的心脏祖细胞）的体外研究来支持，以阐明基本机制。该方法将创新的假设，技术和独特的动物模型与杰出的合作研究人员团队的补充专业知识相结合。拟议的研究很重要，因为预计它将提高我们对心脏再生的理解，锻炼的好处及其减轻疾病的潜力。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见解，并告知与心肌丧失相关的疾病的治疗方法，例如心力衰竭和缺血性心脏病。