Modelling the vasopressin system

基础生物科学对于揭示早期发育和整个生命周期的正常生理和体内平衡控制的机制至关重要。生物科学促进健康优先的目的是在多个层面上深入、综合地了解‘健康系统’，以及在压力和生物或环境挑战下保持健康和健康的因素。(BBSRC 2018年优先事项)健康老龄化取决于生理系统在整个(以及尽管)正常生活所带来的一系列急性和慢性挑战和侮辱中维持身体功能的能力。其中一个关键系统是通过调节荷尔蒙加压素的分泌来运作的。这种荷尔蒙在维持恒定的血液容量和恒定的成分(尤其是钠)方面起着至关重要的作用。加压素是由下丘脑中的一小部分神经元制造的，由它们在脑下垂体的神经末梢分泌：它通过对血管的作用来调节血量，通过它在肾脏的作用来调节水分保持。因此，“适当”的分泌量是血容量和钠浓度的函数。在脱水期间，一个健康的系统可以在很长一段时间内保持适当的高水平分泌，尽管脑下垂体中的加压素储备逐渐耗尽。我们的目的是了解(I)加压素系统在慢性激发时是如何发挥作用的，以及(Ii)对该系统的侮辱如何导致功能紊乱。我们将利用实验室大鼠的实验数据建立加压素系统的计算模型。大鼠的加压素系统与人类非常相似--这是一个重要的系统，在整个哺乳动物进化过程中一直被密切保守--在大鼠身上进行的研究是可能的，但不能在人身上进行。这些研究将包括记录不同慢性条件下加压素细胞的电活动，并研究它们对急性挑战的反应。通过一个详细而准确的加压素系统计算模型，我们将能够评估对该系统的模拟侮辱如何影响其功能。例如，许多神经元在长时间被强烈激活时容易受到损害。在加压素系统中，这可能意味着对钠水平最敏感的细胞是最有可能在长时间不喝水或过量摄入盐的情况下死亡的细胞。当它们死亡时，存活的细胞将受到更大的需求--因此变得更加活跃--导致进一步的细胞损失。在极端情况下，这种恶性循环可能会升级，导致加压素系统突然崩溃。我们认为，该系统有许多内置的机制，以减少这种情况发生的危险。具体地说，电池之间相互通信，通过这样做，它们可以公平地“分担负载”。我们将建立这个相互交流系统的模型，作为我们的加压素系统完整模型的一部分，并对其进行实验测试。有了一个完整的模型，我们将能够系统地探索可能导致长期问题的加压素系统的脆弱性。我们还预计，更好地了解系统如何变得功能失调将有助于识别慢性功能障碍的早期预警迹象。

"Fundamental bioscience is vital to revealing the mechanisms underlying normal physiology and homeostatic control during early development and across the lifespan into old age. The Bioscience for Health priority aims to achieve a deep, integrated understanding of the 'healthy system' at multiple levels, and of the factors that maintain health and wellness under stress and biological or environmental challenge." (BBSRC Priorities 2018)Healthy aging depends on the ability of physiological systems to sustain bodily functions throughout (and despite) the succession of acute and chronic challenges and insults that a normal life entails. One key system operates through the regulated secretion of the hormone vasopressin. This hormone has an essential role in maintaining a constant blood volume with a constant composition (especially of sodium).Vasopressin is made by a small population of neurons in the hypothalamus and is secreted from their nerve terminals in the pituitary gland: it regulates blood volume by its actions on blood vessels and it regulates water retention by its actions at the kidney. The "appropriate" level of secretion is thus a function of blood volume and sodium concentration. During dehydration a healthy system can maintain an appropriately elevated secretion for long periods, despite progressive depletion of the pituitary stores of vasopressin. However, disorders of this system commonly arise during aging, with a substantial impact on quality of life and mortality.Our aim is to understand (i) how the vasopressin system functions during chronic challenge, and (ii) how insults to this system can lead to disturbed function. We will develop computational models of the vasopressin system using experimental data from laboratory rats. The vasopressin system in the rat is very like that of the human - this is an important system that has been closely conserved throughout mammalian evolution - and studies in rats are possible that cannot be performed in people. These studies will involve recording the electrical activity of vasopressin cells in different chronic conditions and studying their responses to acute challenge.With a detailed and accurate computational model of the vasopressin system we will be able to assess how simulated insults to the system affect its functionality. For example, many neurons are vulnerable to damage when they are strongly activated for prolonged periods. In the vasopressin system, this is likely to mean that the cells that are most sensitive to sodium levels are the cells most likely to die during prolonged periods without drinking or with excessive salt intake. As they die, the surviving cells will be under greater demand - so become more active - leading to further loss of cells. In extreme cases this vicious cycle can escalate, leading to a sudden collapse of the vasopressin system. We think that the system has a number of mechanisms built into it to reduce the danger of this happening. In particular, the cells communicate with each other, and by doing so they can 'share the load' equitably. We will build a model of this system of intercommunication as part of our complete model of the vasopressin system, and test it experimentally.With a complete model we will be able to systematically explore the points of vulnerability of the vasopressin system that can lead to long term problems. We expect also, that a better understanding of exactly how the system can become dysfunctional will help to identify early warning signs of chronic dysfunction.