Developing a digital twin of 3D vascular systems to study haemorrhagic viral diseases

我们将开发一个数字孪生的3D微血管类器官培养系统，以研究出血性疾病。生物数字双胞胎是一种计算机模拟，旨在模拟实验系统或体内组织的所有方面。在这里，我们采用基于个体的方法，模拟每个细胞，使双胞胎能够捕获细胞间的相互作用以及整个组织的动态。开发数字孪生模型的优势包括可以快速轻松地探索大参数范围，远远超出实验研究的能力，也可以在无法访问的制度中进行探索。重要的是，越来越多的人认识到数字双胞胎的使用可以减少对动物实验的需求，这些实验涉及生物科学和药物开发。我们将利用数字双胞胎来研究微血管系统（毛细血管系统）的功能障碍，并借鉴共同主管保拉坎帕诺洛博士的实验结果。在许多常见的病毒性疾病中，微血管病变可产生额外的并发症。我们将集中讨论热带疾病登革热，虽然这种疾病大多是温和的疾病，但可以发展为危及生命的出血性疾病。导致微血管屏障破坏的确切机制，导致观察到的急性渗漏和低血容量性休克，只是部分阐明。毛细血管系统的结构涉及两种关键细胞类型：内皮细胞和周细胞，Campagnolo博士首次证明周细胞功能障碍是登革热出血的驱动因素。特别是，她观察到循环蛋白NS1影响周细胞的功能。我们将关注这些结果，并构建周细胞和内皮细胞群体的模拟。我们将在3D球体内模拟这些群体，研究细胞的自组织和生存能力。我们将探讨NS1治疗，并解释观察到的周细胞行为变化（包括粘附和收缩性变化）如何改变组织功能。其目的是在不需要实验的情况下给出疾病进展的机械解释。然而，这些模型将根据实验数据进行验证和参数化。自组织，特别是组织中的细胞分选是另外一个广泛和当前生物学兴趣的领域，本研究将解决收缩性控制的相对重要性和粘附强度在这个关键过程中的差异。

We will develop a digital twin of 3D microvascular organoid culture systems to investigate haemorrhagic diseases. A biological digital twin is a computer simulation designed to mimic all aspects of an experimental system or in vivo tissue. Here we adopt an individual-based approach where each cell is simulated, enabling the twin to capture cell-cell interactions as well as whole tissue dynamics. The advantages of developing a digital twin include that large parameter ranges can be explored quickly and easily far beyond the capacity of experimental investigation and also in regimes that would be inaccessible. Importantly there is increasing recognition that the use of digital twins can reduce the need for animal experimentation with interest spanning biological science and pharmaceutical drug development.We will use the digital twin to look at dysfunctions of the microvasculature (capillary systems) drawing on the experimental results of the co-supervisor Dr Paola Campagnolo. In many common viral diseases additional complications can be generated by microvasculature pathologies. We will focus on the tropical disease Dengue, which although mostly a mild disease can progress to a life-threatening haemorrhagic disease. The precise mechanisms leading to the disruption of the microvascular barrier leading to the observed acute leakage and hypovolemic shock are only partially elucidated. There are two key cell types involved in the structures of capillary system: endothelial cells and pericytes, and Dr Campagnolo has demonstrated for the first time that pericyte dysfunction is a driver in dengue haemorrhage. Specifically, she observed that the circulating protein NS1 affects pericyte function.We will focus on these results and construct a simulation of populations of pericytes and endothelial cells. We will simulate these populations within the 3D spheroids looking at cellular self-organisation and at viability. We will explore NS1 treatment and explain how the observed changes in pericyte behaviour (including changes in adhesion and contractility) would alter tissue functionality. The aim is to give mechanistic explanations of disease progression without the need for experiment. The models will, however, be validated against and parameterised from experimental data. Self-organisation, specifically cell sorting in tissues is additionally an area of broad and current biological interest and this study will resolve the relative importance of contractility control and differences in adhesion strength in this key process.