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。虽然大多数患者在最初的事件中存活下来，但成人心脏的生理性再生远远不足以弥补严重的心肌损失。一些高等生物，如斑马鱼，在损伤后能够完全和充分地再生心肌。此外，小鼠在出生后不久就能再生心脏。尽管成年人和成年小鼠缺乏这种心脏再生的潜力，但人们对了解心脏再生如何发生非常感兴趣，这样我们就可以在人类中激活这一过程，以更好地治疗心肌梗死后的患者。蝾螈肢体在截肢后可以完全再生，这种再生主要依赖于神经活动。无论是机械消融还是经典的非选择性毒蕈碱拮抗剂阿托品，都会破坏蝾螈断肢的显著再生能力，这表明神经活动至少对某些类型的器官再生至关重要。这项研究验证了一个假设，即新生小鼠的心脏再生也依赖于神经信号。我们的初步数据表明，在接触阿托品后，接受根尖切除的斑马鱼无法在切除平面以下再生心脏。在心肌细胞再生过程中，细胞周期再进入和增殖所需的必需蛋白显著增加

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.