Hemodynamic Flow-Mediated Myocardial Reprogramming Impacts Cardiac Development

项目总结 心脏形态发生是一个复杂的过程，不仅受细胞、分子和遗传因素的影响 但也有环境因素的影响，如血流动力学流量。这些发育过程中的干扰 事件会导致先天性心脏病(CHD)，这是人类最常见的出生缺陷，它会影响 几乎每一百个活产婴儿中就有一个，对绝大多数的产前损失负有责任。 尽管已知有几个心脏基因调节程序在心脏疾病中发挥重要作用 到目前为止，特定的致病基因只占冠心病患者的10%左右，这表明 其他遗传和环境因素，包括生物物理力，可能对此起到作用。 疾病。因此，阐明了生物物理因素如何影响的细胞、分子和生理学基础 心脏形态发生学可能为患者的预防、诊断和治疗提供新的见解 易患冠心病。尽管最近的研究表明，心肌细胞等生物力学力量 收缩能力和心内血流可能调节心脏形态发生，这是潜在的 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，我们认为血流动力的改变可能会影响 通过“适应性细胞重编程”过程识别心肌细胞，其中心肌细胞 保持足够的细胞可塑性，能够重新编程，以改变其细胞命运 环境影响。因此，这些拟议研究的总体目标是阐明心脏是如何 感知生物机械力并传递它们的信号来控制心肌细胞的重新编程。结果是 这些研究不仅将阐明血流动力学力量如何适应性地改变心肌细胞的命运 在心脏发育过程中引导心脏形态发生，还提供了对心脏如何 对心肌细胞重新编程以响应由于结构或功能引起的血流动力学扰动 心脏缺陷。 好了！

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. !