Statistical modelling of in vivo immune response dynamics in zebrafish to multiple stimuli

斑马鱼的胚胎在光学上是透明的，这使我们能够实时地看到生物过程。在这里，我们将研究先天免疫反应如何处理对鱼类健康的不同威胁。我们将特别研究鱼对受伤和癌症的反应。在这两种情况下，免疫反应系统的细胞都被吸引到伤口部位或肿瘤/癌细胞的位置，确定实现这一目标的精确方式是我们研究的基本目标之一。我们将结合使用显微镜和数学模型来了解免疫系统是如何感知和响应这些刺激的。我们将重建机制模型，捕捉细胞如何反应并根据观察到的数据做出决定。为此，我们还将开发新的统计和计算工具。这将允许我们分析这个项目过程中产生的复杂数据。我们对细胞如何做出决定以及我们如何引导这种行为非常感兴趣。为此，我们还将选择性地干扰和探测直接影响免疫细胞如何对刺激作出反应并向目标移动的分子相互作用网络。至关重要的是，数学模型还将使我们能够评估，当免疫反应受到不止一种刺激时，它是如何被调节的。这是一个完全未解决的问题，但具有重要的基础和生物医学意义：例如，手术仍然是治疗许多癌症的重要方法之一，我们的初步分析表明，损伤（手术）和癌症对先天免疫反应细胞的影响不同。更一般地说，这项研究将开发一个可以应用于其他环境的平台，在这些环境中，我们想要分析生物体内部的生物过程。这些调查将大大受益于作为这项研究的一部分而开发的统计、计算和图像分析工具和协议。

Zebrafish embryos are optically transparent and allow us to visualize biological processes in real time. Here we will study how the innate immune response deals with different threats to the fish's health. In particular we will study the response to wounding and to cancer in the fish. In both cases cells of the immune response system are drawn to the wound site or the location of the tumor/cancer cell and determining the precise way in which this is achieved is one of the fundamental aims of our research. We will use a combination of microscopy and mathematical modelling in order to understand how the immune system senses and responds to such stimuli. We will reconstruct mechanistic models that capture how cells react and reach decisions from the observed data. To this end we will also develop new statistical and computational tools. These will allow us to analyze the complex data generated over the course of this project. We are very interested in how cells make decisions and how we can guide such behaviour. To this end we will also selectively interfere with and probe molecular interaction networks that affect directly how the immune cells respond to stimuli and move towards their target.Mathematical models will, crucially, also allow us to assess how the immune response is regulated if it receives more than one stimulus. This is a completely unsolved problem but one of great fundamental and biomedical importance: for example surgery is still one of the important therapeutic approaches against many cancers and our initial analyses have shown that wounding (surgery) and cancer affect cells of the innate immune response differently. More generally, this research will develop a platform that can be applied also in other contexts, where we want to analyze biological processes inside living organisms. Such investigations will benefit greatly from the statistical, computational and image analysis tools and protocols that are developed as part of this research.