A computational framework to investigate the mechanical role of the extracellular matrix in tissue development and disease

研究细胞外基质在组织发育和疾病中的机械作用的计算框架

• 批准号: NC/T002425/1
• 负责人: Nargess Khalilgharibi
• 金额: $ 17.57万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=NC%2FT002425%2F1
• 关键词: computational; framework; investigate; mechanical; role

The tissues in the body are lined by the extracellular matrix (ECM), a meshwork of proteins that acts as a physical support and provides them with biochemical and mechanical cues. Cells have the ability to change the composition and mechanical properties of the ECM through synthesis, degradation and rearrangement of its components. These changes are crucial for developing flat sheets of tissues into complex 3-dimensional structures. In adult life, correct ECM composition is vital for maintaining tissue shape and ensuring its correct function. Dysregulation in ECM composition and mechanical properties, either during development or later in life and as a result of disorders such as diabetes, can lead to severe pathological condition, such as kidney failure, hearing loss and blindness.So far, most of the knowledge about the role of ECM in tissue growth and function has come from animal experiments. However, it is still not possible to follow live changes in ECM structure and composition in the same animal. Therefore, a single study looking at these changes, either through a developmental process or during disease progression, requires sacrifice of many animals. Recently, scientists have been trying to grow organ-like tissues (i.e. organoids) in the lab. These organoids have high clinical potential and can replace animal research in the fields of tissue development and disease. However, majority of current organoid culture techniques rely on the use of extracellular matrix scaffolds derived from animals, which affects their reproducibility and hinders their translation into clinics. Scientists are working to replace these animal-derived matrices with synthetic ones, a process that requires large amount of time and resources.I propose to develop a multiscale computational platform of tissue growth and function, with explicit implementation of the extracellular matrix mechanics. This will allow researchers to model the growth of their tissue of interest, test the effect of different conditions on its growth and function, and design a minimum set of experiments to carry out in the lab, therefore replacing many animal experiments with computer simulations. The model will also allow researchers to simulate growth of organoids in synthetic matrices with different mechanical properties, and identify the optimal properties that can be further fine-tuned experimentally. This will significantly enhance protocol optimisation steps, allowing researchers to easily tailor-design synthetic ECM matrices for growth of different organoids, and eventually fully replace animal matrices with their synthetic counterparts. Finally, the open-source nature of our model will also allow researchers to incorporate their data into the model to capture more sophisticated processes, and therefore significantly reduce animal use.

体内组织由细胞外基质（ECM）内衬，细胞外基质是一种蛋白质网络，充当物理支持并为它们提供生化和机械线索。细胞具有通过其组分的合成、降解和重排来改变ECM的组成和机械性质的能力。这些变化对于将扁平的组织片发育成复杂的三维结构至关重要。在成年生活中，正确的ECM成分对于维持组织形状和确保其正确功能至关重要。细胞外基质（ECM）的组成和力学特性的失调，无论是在发育过程中，还是在生命后期，以及由于疾病如糖尿病，都可能导致严重的病理状态，如肾功能衰竭、听力损失和失明。然而，仍然不可能在同一动物中跟踪ECM结构和组成的实时变化。因此，通过发育过程或疾病进展观察这些变化的单一研究需要处死许多动物。最近，科学家们一直试图在实验室中培养器官样组织（即类器官）。这些类器官具有很高的临床潜力，可以取代组织发育和疾病领域的动物研究。然而，目前大多数类器官培养技术依赖于使用来源于动物的细胞外基质支架，这影响了它们的可重复性并阻碍了它们向临床的转化。科学家们正在努力用合成基质取代这些动物源性基质，这一过程需要大量的时间和资源。我建议开发一个多尺度的组织生长和功能计算平台，明确实现细胞外基质力学。这将使研究人员能够模拟他们感兴趣的组织的生长，测试不同条件对其生长和功能的影响，并设计在实验室中进行的最小实验集，从而用计算机模拟取代许多动物实验。该模型还将允许研究人员模拟具有不同机械特性的合成基质中类器官的生长，并确定可以通过实验进一步微调的最佳特性。这将显著增强方案优化步骤，使研究人员能够轻松地为不同类器官的生长量身定制合成ECM基质，并最终用合成基质完全取代动物基质。最后，我们模型的开源性质也将允许研究人员将他们的数据纳入模型，以捕获更复杂的过程，从而显着减少动物使用。