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

开发 3D 血管系统的数字孪生来研究出血性病毒性疾病

• 批准号: NC/Y500586/1
• 金额: $ 17.2万
• 依托单位: University of Surrey
• 依托单位国家: 英国
• 项目类别: Training Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=NC%2FY500586%2F1
• 关键词: Developing; digital; twin; 3D; vascular

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.

我们将开发 3D 微血管类器官培养系统的数字双胞胎来研究出血性疾病。生物数字孪生是一种计算机模拟，旨在模拟实验系统或体内组织的各个方面。在这里，我们采用基于个体的方法，对每个细胞进行模拟，使双胞胎能够捕获细胞与细胞的相互作用以及整个组织的动态。开发数字孪生的优点包括可以快速、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情况下进行。重要的是，人们越来越认识到，数字孪生的使用可以减少对生物科学和药物开发感兴趣的动物实验的需求。我们将利用数字孪生根据实验结果来观察微脉管系统（毛细血管系统）的功能障碍联合导师保拉·坎帕尼奥洛 (Paola Campagnolo) 博士的研究。在许多常见的病毒性疾病中，微血管病变可能会产生额外的并发症。我们将重点关注热带疾病登革热，虽然这种疾病大多是一种轻微的疾病，但可能会发展为危及生命的出血性疾病。微血管屏障破坏导致观察到的急性渗漏和低血容量性休克的确切机制仅部分阐明。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。具体来说，她观察到循环蛋白 NS1 影响周细胞功能。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 球体中模拟这些群体，观察细胞自组织和活力。我们将探索 NS1 治疗并解释观察到的周细胞行为变化（包括粘附性和收缩性的变化）如何改变组织功能。目的是在不需要实验的情况下给出疾病进展的机制解释。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也是当前广泛的生物学兴趣领域，这项研究将解决收缩性控制和粘附强度差异在这一关键过程中的相对重要性。