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.

人类心力衰竭进展的一个主要因素是成人心脏无法自我修复 受伤后。因此，诱导心脏再生的策略具有重大意义。此前，我们 研究小组证明，与成年人的心脏不同，出生后早期哺乳动物的心脏能够 损伤后通过现有心肌细胞增殖再生。我们已经证明，Meis 1，a TALE家族同源结构域蛋白，通过激活以下基因的表达促进出生后从细胞周期中退出： 细胞周期蛋白依赖性抑制剂p16和p21。我们，沿着其他调查人员，已经确定了一个 另外的信号传导机制的多样性，其起允许或限制增殖的作用（增加 机械负荷、氧合、DNA损伤反应等）。这表明Meis 1并不是单独工作的， 但必须作为调节过程网络的一部分，尽管，连接这些过程的分子机制 过程基本上是未知的。展望未来，我们目前提案的目标是整合Meis 1- 通过识别Meis 1辅因子， 监管部门具体地说，我们将集中于定义Meis 1与其辅因子Hoxb 13的功能相互作用， 出生后心脏和钙激活蛋白磷酸酶钙调神经磷酸酶（CN）在 调节这种相互作用及其后果。出生后心脏负荷的增加是已知的， 导致心肌细胞肥大和收缩性增加的信号级联。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 表明CN还与Meis 1/Hoxb 13复合物一起抑制增殖性生长。 因此，出生后CN的激活提供了一个信号，有助于将心脏生长的机制从 从增生到肥大我们假设CN促进出生后心肌细胞的停滞， 通过介导Meis 1和HoxB 13的核转位来调节细胞周期。我们的实验旨在（1） 检查Hoxb 13作为Meis 1辅因子的作用，（2）定义Meis 1的CN调节机制， Hoxb 13功能，和（3）测试CN控制出生后细胞周期和心脏再生的能力。 这些研究将提供基本的见解之间的协调联系的性质产后 心脏负荷增加导致肥大，抑制心脏修复能力。