Calcineurin Regulates Cardiomyocyte Cell Cycle Through Meis1 and Hoxb13

人类心力衰竭进展的一个主要因素是成人心脏不能自我修复。 在受伤之后。因此，诱导心脏再生的策略是非常有意义的。此前，我们的 研究小组证明，与成年心脏不同，哺乳动物出生后早期的心脏能够 损伤后通过现有心肌细胞的增殖进行再生。我们已经证明了Meis1，a TALL家族同源结构域蛋白，通过激活表达，促进出生后退出细胞周期 细胞周期蛋白依赖性抑制物p16和p21。我们和其他调查人员一起，继续发现了一个 允许或限制扩散的其他信号机制的多样性(增加 机械负荷、氧合作用、DNA损伤反应等)。这表明Meis1不是单独工作的， 但必须作为调控过程网络的一部分，尽管连接这些过程的分子机制 过程在很大程度上是未知的。展望未来，我们当前提案的目标是整合MEIS1- 通过识别Meis1辅因子和Meis1与更广泛的出生后信号网络的依赖机制 监管者。具体地说，我们将重点定义Meis1与其辅因子HOXB13在 生后心脏及钙激活蛋白磷酸酶钙调神经磷酸酶(CN)的作用 规范这种相互作用及其后果。众所周知，出生后心脏负荷的增加会引发 导致心肌细胞肥大和收缩能力增强的信号级联反应。CN的激活 提供促进心肌细胞肥大生长的基本信号。我们的初步研究 提示CN还与Meis1/HOXB13复合体一起作用，以抑制增殖生长。 因此，出生后CN的激活提供了一种信号，有助于将心脏生长的机制从 从增生性到肥大性。我们假设CN促进出生后心肌细胞的停滞 通过介导Meis1和HOXB13的核转位实现循环。我们的实验设计是为了(1) 研究HOXB13作为Meis1辅助因子的作用，(2)确定Meis1和Meis1的CN调节机制 HOXB13的功能；(3)检测CN对出生后细胞周期和心脏再生的调控能力。 这些研究将提供对出生后之间协调联系的本质的基本见解 心脏负荷增加，导致肥大，并抑制心脏的修复能力。

A major factor in the progression to heart failure in humans is the inability of the adult heart to repair itself following injury. As a result, strategies to induce heart regeneration are of significant interest. Previously, our group demonstrated that, unlike the adult heart, the early postnatal mammalian heart is capable of regeneration following injury through proliferation of existing cardiomyocytes. We have shown that Meis1, a TALE family homeodomain protein, promotes postnatal withdrawal from cell cycle by activating expression of the cyclin dependent inhibitors p16 and p21. We, along with other investigators, have gone on to identify a diversity of additional signaling mechanisms that act to either permit or restrict proliferation (increased mechanical load, oxygenation, DNA damage response, etc.). This suggests that Meis1 does not work alone, but must act as part of a network of regulatory processes, although, the molecular mechanisms linking these processes are largely unknown. Moving forward, the goal of our current proposal is to integrate Meis1- dependent mechanisms with the wider postnatal signaling network by identifying Meis1 cofactors and regulators. Specifically, we will focus on defining the functional interaction of Meis1 with its cofactor Hoxb13 in the postnatal heart and the role played by the Ca2+-activated protein phosphatase calcineurin (CN) in regulating this interaction and its consequences. The postnatal increase in cardiac load is known to initiate a signaling cascade that leads to cardiomyocyte hypertrophy and increased contractility. Activation of CN provides fundamental signals that promote hypertrophic growth of cardiomyocytes. Our preliminary studies suggest that CN also works in conjunction with a Meis1/Hoxb13 complex to suppress proliferative growth. Thereby, postnatal activation of CN provides a signal that helps switch the mechanism of cardiac growth from hyperplastic to hypertrophic. We hypothesize that CN promotes postnatal arrest of cardiomyocyte cell cycle by mediating nuclear translocation of Meis1 and HoxB13. Our experiments are designed to (1) examine the role of Hoxb13 as a Meis1 co-factor, (2) define the mechanism of CN regulation of Meis1 and Hoxb13 function, and (3) test the ability of CN to control postnatal cell cycle and heart regeneration. These studies will provide fundamental insights into the nature of the coordinating link between the postnatal increase in cardiac load that drives hypertrophy, and suppression of the heart’s capacity for repair.