Computational modelling of type I collagen synthesis to investigate age-related tissue fibrosis and tissue degeneration

I型胶原是人类体内含量最丰富的蛋白质，也是结缔组织的主要成分。这种蛋白质的半衰期很长，周转率很低。在衰老和慢性病中，胶原蛋白的合成会严重失调，使胶原蛋白的合成增加数百倍。胶原蛋白的过度产生会导致器官纤维化和组织硬化，导致临床和行动不便。造成这种戏剧性上调的机制很复杂，还没有完全弄清楚。I型胶原的生物合成在转录、翻译和转录后/翻译水平受到严格调控，以防止有害的合成。有证据表明，与年龄相关的I型胶原调节失调会导致COL1A1基因衍生的异常同源三聚体的产生。同源三聚体不易降解，在老化过程中可能会影响组织的动态平衡。这个项目旨在阐明I型胶原的分子控制系统如何随着年龄的增长而功能失调，以及这是如何导致胶原合成的异常变化的。I型胶原转录后调控和翻译调控的全面计算模型的建立将有助于理解这一过程。系统生物学方法将使用已发表的数据和以前的实验结果进行应用，然后使用从细胞培养中的目标实验获得的数据进行进一步改进。通过这样做，可以预测有利于生产均三聚体的条件，并且将更好地理解导致大量I型胶原过度生产或生产不足的情况。

Type I collagen is the most abundant protein in humans and the main component of connective tissues. The protein has a long half-life and its turnover is low. Collagen synthesis can become severely dysregulated in ageing and chronic disease, increasing collagen synthesis several hundred-fold. Over-production of collagen causes organ fibrosis and tissue sclerosis, leading to clinical and mobility problems. The mechanisms which are responsible for this dramatic upregulation are complex and not yet entirely understood. Type I collagen biosynthesis is strictly regulated at transcriptional, translational and post-transcriptional/translational levels to prevent detrimental synthesis. Evidence suggests that age-related dysregulation of type I collagen can result in the production of an abnormal homotrimeric form, derived from the COL1A1 gene. The homotrimer is resistant to degradation and likely to affect tissue homeostasis during ageing. This project aims to elucidate how type I collagen's molecular control system becomes dysfunctional with age and how this results in aberrant changes in collagen synthesis. The creation of a comprehensive computational model of the post-transcriptional and translational regulators of type I collagen will aid in understanding this process. A systems biology approach will be applied using published data and previous experimental findings, and then further refined using data obtained from targeted experiments in cell cultures. In doing so conditions favouring production of the homotrimeric form can be predicted and the situations that lead to substantial type I collagen over- or under- production will be better understood.