Role of Nerves in Guiding Cardiac Regeneration

描述（由申请人提供）：每年有超过一百万的美国人患有心肌梗死。虽然大多数患者在初始事件中存活，但成人心脏的生理再生严重不足以补偿心肌的严重损失。一些高等生物，如斑马鱼，能够在损伤后完全和充分地再生心肌。此外，小鼠在出生后早期就能够再生心脏。虽然成年人和成年小鼠缺乏这种心脏再生潜力，但人们对了解心脏再生如何发生非常感兴趣，以便我们可以激活人类的这一过程，以更好地治疗心肌梗死后的患者。蝾螈的肢体在截肢后可以完全再生，这种再生主要取决于神经活动。机械消融以及经典的非选择性毒蕈碱拮抗剂阿托品都能消除蝾螈断肢的显著再生能力，表明神经活动至少对某些类型的器官再生至关重要。[The拟议的研究测试了新生小鼠心脏再生也依赖于神经信号传导的假设。 我们的初步数据表明，暴露于阿托品后，接受了心尖切除术的斑马鱼无法在切除平面以下再生心脏。心肌细胞再生中细胞周期重入和增殖所需的必需蛋白质明显减少， 与对照组相比，阿托品处理的心脏的心室心肌细胞下调。总之，这些数据强烈暗示了神经在损伤后心脏再生中的作用。最近的实验表明，出生后不久，新生小鼠也可以在受伤后再生心脏。这一惊人的现象表明，哺乳动物系统至少在这一关键时期保持了自我修复的能力。为了研究胆碱能神经在哺乳动物心脏再生中的作用，我们计划研究阿托品和胆碱能特异性神经营养因子neurturin基因敲除对新生小鼠心脏再生的影响。[Fuxin，蝾螈中神经依赖性肢体再生部分由分泌蛋白Agr 2介导。与蝾螈肢体一样，我们的初步数据表明，Agr 2可以部分挽救去神经斑马鱼的心脏再生。在这里，我们测试了Agr2施用挽救新生小鼠中的心脏再生的假设。利用新生小鼠心脏再生模型将是我们初步斑马鱼实验的有力补充。小鼠心脏与人类心脏更相似，因此可以为人类心脏再生潜力提供重要见解。从拟议的研究中获得的见解对于实现理解心脏如何在损伤后再生的目标至关重要。

DESCRIPTION (provided by applicant): Over one million Americans suffer from myocardial infarction each year. Although most patients survive the initial event, the physiologic regeneration in the adult heart is grossly inadequate to compensate for the severe loss of myocardium. Some higher organisms, such as zebrafish, are capable of complete and sufficient regeneration of the myocardium following injury. Furthermore, mice are capable of regenerating their hearts early after birth. Although adult humans and adult mice lack this cardiac regeneration potential, there is great interest in understanding how regeneration can occur in the heart so that we can activate this process in humans to better treat patients following myocardial infarction. The newt limb can completely regenerate after amputation, and this regeneration depends critically upon nerve activity. Both mechanical ablations as well as the classic non-selective muscarinic antagonist, atropine, abolish the dramatic regenerative capacity of severed limbs in newts, demonstrating that nerve activity is crucial for at least some types of organ regeneration. [The proposed research tests the hypothesis that cardiac regeneration in the neonatal mouse is also dependent upon nerve signaling.] Our preliminary data demonstrate that following exposure to atropine, zebrafish that had undergone apical resection were unable to regenerate their hearts below the resected plane. Essential proteins required for cell cycle re-entry and proliferation in cardiomyocyte regeneration were significantly downregulated in the ventricular cardiomyocytes of atropine treated hearts compared to control. Taken together, these data strongly implicate a role for nerves in cardiac regeneration following injury. Recent experiments have shown that shortly after birth, neonatal mice can also regenerate their hearts following injury. This striking phenomenon indicates that the mammalian system retains the ability to repair itself at least during this critical period. In order to invesigate the role that cholinergic nerves play in mammalian cardiac regeneration we plan to study the effects of atropine and gene knockout of the cholinergic specific neurotrophic factor, neurturin, on cardiac regeneration in the neonatal mouse. [Futhermore, nerve-dependent limb regeneration in the newt is partially mediated by the secreted protein Agr2. As in the newt limb, our preliminary data demonstrates that Agr2 can partially rescue cardiac regeneration in denervated zebrafish. Here, we test the hypothesis that Agr2 administration rescues cardiac regeneration in the neonatal mouse.] Utilizing the neonatal mouse model of cardiac regeneration will be a powerful supplement to our preliminary zebrafish experiments. The mouse heart more closely resembles the human heart and therefore can provide important insight into the cardiac regenerative potential in humans. The insights from the proposed research are critically important for reaching the goal of understanding how the heart can be regenerated following injury.