Mechanisms of change, cellular responses of the fish heart to physiological stress

一颗强大的心脏是维持生命必不可少的。有趣的是，脊椎动物的心脏能够改变其形式和功能，以满足动物不断变化的需求。例如，运动训练会导致心脏变大，每跳一次就会泵出更多的血液。心脏的这种变化提高了血液输送到组织的速度，并使体力活动速度更快。心脏损伤或疾病后，心脏也会发生适应不良的变化。在这里，心脏形成疤痕组织，肌肉数量减少，导致心脏虚弱，功能受损。虽然上述适应性和非适应性变化已经在器官水平上得到了很好的描述，但对负责启动和调节它们的细胞通路知之甚少。这项拟议的研究项目的重点是控制脊椎动物心脏结构和功能能力变化的机制。我们将专门研究鲑鱼心脏和斑马鱼心脏对温度变化的重塑反应，以及鳗鱼心脏在没有氧气的情况下发挥作用的能力。这些鱼类的心脏是检查心脏重塑的非常好的模型，因为它们可以在很大范围的生理条件下保持功能，也可以在会使人类心脏停止跳动的条件下发挥功能。在第一项研究中，我们将检测鲑鱼心脏和斑马鱼心脏对环境温度变化的胶原含量的反应能力。在人类中，胶原蛋白的积聚会导致心力衰竭，因为心脏会变得僵硬，无法在两次跳动之间放松。通过确定调控鱼心脏胶原沉积的细胞通路所获得的知识，可能有助于开发控制心脏损伤患者结缔组织形成的治疗方法。鲑鱼的冷驯化也会使心肌产生更多的力量。在第二项研究中，我们将研究细胞机制如何随着冷驯化而变化，并看看我们是否能在温暖驯化的鱼的心脏上重现这种反应。最后，在最近的一项研究中，我们证明了鳗鱼的心脏可以在没有氧气的情况下保持功能超过16小时。考虑到人类的心脏在缺氧几分钟内就开始死亡，这是一个令人惊讶的能力。在第三项研究中，我们将确定使鳗鱼心脏在没有氧气的情况下进行收缩的细胞机制(S)。这种知识在心脏病发作后或移植期间保存心脏组织的策略的开发中具有应用价值。总之，这些研究将为调节心脏功能和适应的过程提供新的见解。

A powerful heart is essential to supporting life. Interesting, the vertebrate heart is able to change both its form and function to meet the changing requirements of the animal. For example, exercise training will cause the heart to increase in size and pump more blood per beat. This change to the heart increases the rate at which blood can be delivered to the tissues and enables a higher rate of physical activity. The heart can also undergo maladaptive changes following cardiac injury or disease. Here, scar tissue forms in the heart and the amount of muscle decreases resulting in a weakened heart with impaired function. While the above adaptive and maladaptive changes have been well described at the organ level, there is less known of the cellular pathways responsible for initiating and regulating them. The proposed research project is focused on the mechanisms responsible for controlling changes in the structure and functional capacity of the vertebrate heart. We will specifically examine the remodeling response of the trout heart and zebrafish heart to a change in temperature and the ability of the hagfish heart to function without oxygen. The hearts of these fish species are very good models to examine cardiac remodeling as they can maintain function across a significant range of physiological conditions and also function under conditions that would stop the human heart. In the first study we will examine the ability of the trout heart and zebrafish heart to manipulate collagen content in response to a change in environmental temperature. In humans, a build-up of collagen can lead to heart failure as the heart becomes stiff and unable to relax between beats. Knowledge gained by characterizing the cellular pathways that regulate collagen deposition in the hearts of fish may help in developing treatments to control connective tissue formation in patients who have suffered cardiac injury. Cold acclimation of trout also causes the heart muscle to generate more force. In the second study we will examine how the cellular machinery changes with cold acclimation and see if we can reproduce this response in warm acclimated fish hearts. Finally, in a recent study we have demonstrated the hagfish heart can maintain function without oxygen for more than 16 h. This is an amazing ability considering that the human heart begins to die within minutes of oxygen deprivation. In the third study, we will determine the cellular mechanism(s) that enable the hagfish heart to power contraction without oxygen. Such knowledge has application in the development of strategies to preserve heart tissue following a heart attack or during transplant. Together these studies will provide novel insight into the processes that regulate cardiac function and adaptation.