Calcineurin Regulates Cardiomyocyte Cell Cycle Through Meis1 and Hoxb13

钙调神经磷酸酶通过 Meis1 和 Hoxb13 调节心肌细胞周期

• 批准号: 10371869
• 负责人: Hesham Sadek
• 金额: $ 40.5万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371869
• 关键词: Address; Adult; Aging; Binding; Birth; CDK6-associated protein p18; Calcineurin; Calcineurin inhibitor; Cardiac; Cardiac Myocytes; Cell Cycle; Cell Cycle Arrest; Cell Cycle Regulation; Cells; Complex; DNA Binding; DNA Damage; Data; Event; Failure; Family; Genetic Transcription; Goals; Growth; HOX protein; Heart; Heart failure; Homeodomain Proteins; Human; Hyperplasia; Hypertrophy; Injury; Knockout Mice; Knowledge; Link; Mediating; Messenger RNA; Modeling; Molecular; Myocardial Infarction; Myocardium; Nature; Neonatal; Nuclear Localization Signal; Nuclear Translocation; Phospho-Specific Antibodies; Play; Process; Protein Dephosphorylation; Protein phosphatase; Proteins; Regenerative capacity; Regulation; Research; Research Personnel; Role; Serine Phosphorylation Site; Signal Transduction; Site; Testing; Therapeutic; Time; Transcriptional Regulation; Withdrawal; Work; calcineurin phosphatase; cardiac regeneration; cofactor; design; experimental study; homeodomain; insight; interest; loss of function; mechanical load; mouse model; overexpression; postnatal; regeneration following injury; repaired; response; transcription factor

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.

人类心力衰竭发展的主要因素是成人心脏无法修复 受伤后。结果，诱导心脏再生的策略具有重大关注。以前，我们的 小组表明，与成人心脏不同，早期的产后哺乳动物心脏能够 通过现有心肌细胞的增殖而受伤后的再生。我们已经证明了Meis1，一个 故事家族同源域蛋白，通过激活表达来促进产后从细胞周期中提取 细胞周期蛋白依赖性抑制剂p16和p21。我们与其他调查人员一起继续确定 允许或限制增殖的其他信号传导机制的多样性（增加） 机械载荷，氧合，DNA损伤响应等）。这表明Meis1不单独工作， 但是必须充当监管过程网络的一部分 过程在很大程度上未知。向前迈进，我们当前建议的目标是整合Meis1- 通过识别MEIS1辅助因子和 监管机构。具体而言，我们将专注于定义Meis1与其辅因子HOXB13的功能相互作用 Ca2+活化蛋白磷酸蛋白酶钙调蛋白（CN）在产后心脏和作用 调节这种互动及其后果。已知心脏负荷的产后增加会引发A 信号级联导致心肌细胞肥大并增加收缩力。 CN的激活 提供基本信号，促进心肌细胞的肥厚性生长。我们的初步研究 建议CN还与MEIS1/HOXB13复合物一起使用以抑制增殖生长。 因此，CN产后激活提供了一个信号，有助于从 增生至肥厚。我们假设CN促进了心肌细胞的产后停止 通过介导MEIS1和HOXB13的核易位循环。我们的实验设计为（1） 检查HOXB13作为MEIS1共同因素的作用，（2）定义MEIS1和MEIS1的CN调控机制 HOXB13功能和（3）测试CN控制产后细胞周期和心脏再生的能力。 这些研究将为产后之间的协调联系的性质提供基本的见解 增加心脏负荷驱动肥大，并抑制心脏修复能力。