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

I型胶原蛋白是人体中最丰富的蛋白质，也是结缔组织的主要成分。这种蛋白质半衰期长，周转率低。胶原蛋白的合成在衰老和慢性疾病中会严重失调，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，导致临床和流动性问题。负责这种戏剧性上调的机制是复杂的，尚未完全理解。I型胶原蛋白生物合成在转录、翻译和转录后/翻译水平上受到严格调控，以防止有害的合成。有证据表明，与年龄相关的I型胶原蛋白失调可导致产生异常的同源三聚体形式，来源于COL 1A 1基因。同源三聚体抗降解，并可能影响衰老过程中的组织稳态。 本项目旨在阐明I型胶原蛋白的分子控制系统如何随着年龄的增长而变得功能失调，以及这如何导致胶原蛋白合成的异常变化。建立一个全面的计算模型的转录后和翻译调节I型胶原蛋白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，然后使用从细胞培养中的靶向实验获得的数据进一步完善。在这样做时，可以预测有利于产生同源三聚体形式的条件，并且将更好地理解导致大量I型胶原过度产生或产生不足的情况。

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.