Hemodynamic Flow-Mediated Myocardial Reprogramming Impacts Cardiac Development

项目摘要 心脏形态发生是一个复杂的过程，不仅是由细胞，分子和遗传介导的 因素，但也环境影响，如血流动力学流量。破坏这些发展 先天性心脏病（CHD）是人类最常见的出生缺陷， 几乎每100个活产婴儿中就有一个死亡，并且是绝大多数产前死亡的原因。 尽管已知几种心脏基因调控程序在心脏疾病中起重要作用， 发展中国家，特定的致病基因迄今仅占冠心病患者的10%左右，这表明 其他遗传和环境病因学，包括生物物理力量，可能有助于这一点 疾病因此，阐明了生物物理因素如何影响的细胞，分子和生理基础 心脏形态发生可能为患者的预防、诊断和治疗提供新的见解 易患冠心病虽然最近的研究表明，生物力学力量，如心肌细胞 收缩力和心内血流动力学可以调节心脏形态发生， 这些生物物理力如何具体促进心脏发育的各个方面的机制 仍有待阐明。在这里，我们认为血液动力学的改变可能会影响 通过“适应性细胞重编程”过程确定心肌细胞的身份， 保持足够的细胞可塑性，能够重新编程，以改变他们的细胞命运， 环境影响。因此，这些拟议研究的总体目标是阐明心脏如何 感知生物力学力并将其信号转换为控制心肌细胞重编程的信号。结果 这些研究不仅将阐明血流动力学如何适应性地改变心肌细胞的命运， 在心脏发育过程中指导心脏形态发生，同时也提供了心脏如何 对心肌细胞进行重编程，以响应由于结构或功能 心脏缺陷 !

PROJECT SUMMARY Cardiac morphogenesis is a complex process that is mediated by not only cellular, molecular and genetic factors but also environmental influences, such as hemodynamic flow. Disruption in these developmental events can result in Congenital Heart Disease (CHD), the most common birth defect in humans, which affects nearly one out of every one-hundred live births and is responsible for the vast majority of prenatal losses. Although several cardiac gene regulatory programs are known to play an important role in cardiac development, specific disease-causing genes so far account for only ~10% of patients with CHD, suggesting that additional genetic and environmental etiologies, including biophysical forces, may contribute toward this disease. Thus, illuminating the cellular, molecular, and physiologic basis of how biophysical factors influence cardiac morphogenesis may provide novel insights into the prevention, diagnosis, and treatment of patients predisposed for CHD. Although recent studies have shown that biomechanical forces such as cardiomyocyte contractility and intracardiac hemodynamic flow may regulate cardiac morphogenesis, the underlying mechanisms of how these biophysical forces specifically contribute to various aspects of cardiac development remains to be elucidated. Here, we propose that alterations in hemodynamic forces may impact cardiomyocyte cell identity through an “adaptive cellular reprogramming” process where cardiomyocytes that retain sufficient cellular plasticity are able to reprogram in order to change their cell fate in response to environmental influences. Thus, the overall goals of these proposed studies are to illuminate how the heart senses biomechanical forces and transduces their signal to control cardiomyocyte reprogramming. The results of these studies will not only elucidate how hemodynamic forces may adaptively alter cardiomyocyte fate during heart development to guide cardiac morphogenesis but also provide insight into how the heart may reprogram cardiomyocytes in response to perturbations in hemodynamic flow due to structural or functional heart defects. !