Role of Nerves in Guiding Cardiac Regeneration

神经在引导心脏再生中的作用

• 批准号: 8594858
• 负责人: Caitlin C O'Meara
• 金额: $ 5.22万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8594858
• 关键词: Ablation; Adult; American; Amputation; Animals; Apical; Atropine; Attenuated; Birth; Cardiac; Cardiac Myocytes; Cell Cycle; Cellular biology; Data; Denervation; Digit structure; Employee Strikes; Event; Excision; Exposure to; Fellowship; Future; Genetic; Goals; Heart; Heart failure; Human; Injury; Limb structure; Mammals; Mechanics; Mediating; Modeling; Molecular Biology; Mus; Muscarinic Antagonists; Myocardial Infarction; Myocardium; Natural regeneration; Neonatal; Nerve; Nervous system structure; Newts; Organism; Pathway interactions; Patients; Physiological; Play; Process; Proteins; Recombinants; Regenerative Medicine; Research; Research Personnel; Resected; Role; Signal Transduction; System; Testing; Training; Ventricular; Work; Zebrafish; cardiac repair; cholinergic; critical period; design; in vivo regeneration; insight; interest; knockout gene; limb regeneration; mouse model; neurotrophic factor; neurturin; organ regeneration; prevent; public health relevance; regenerative; relating to nervous system; repaired; research study; tissue regeneration

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.

描述(申请人提供)：每年有超过一百万的美国人患有心肌梗塞。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严重不足以补偿严重的心肌损失。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，小鼠在出生后能够早期再生它们的心脏。尽管成年人类和成年小鼠缺乏这种心脏再生潜力，但人们对了解心脏如何发生再生非常感兴趣，以便我们能够在人类身上激活这一过程，以更好地治疗心肌梗死后的患者。纽特肢体在截肢后可以完全再生，这种再生在很大程度上依赖于神经活动。机械消融和经典的非选择性毒扁豆碱拮抗剂阿托品，都能消除蝾螈断肢的戏剧性再生能力，表明神经活动对至少某些类型的器官再生至关重要。[这项拟议的研究验证了一种假设，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，在阿托品暴露后，接受根尖切除的斑马鱼无法在切除平面以下再生心脏。心肌细胞再生过程中细胞周期重入和增殖所需的重要蛋白质 与对照组相比，阿托品处理组的心肌细胞表达下调。综上所述，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，新生小鼠出生后不久，也可以在受伤后再生它们的心脏。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着自我修复的能力。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神经土林基因敲除对新生小鼠心脏再生的影响。此外，Newt的神经依赖性肢体再生部分是由分泌蛋白AGR2介导的。就像在Newt肢体中一样，我们的初步数据表明，AGR2可以部分挽救失神经斑马鱼的心脏再生。在这里，我们测试了这样一种假设，即给予AGR2可以挽救新生小鼠的心脏再生。]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。小鼠心脏更接近人类心脏，因此可以提供对人类心脏再生潜力的重要洞察。这项拟议研究的洞察力对于实现了解损伤后心脏如何再生的目标至关重要。