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

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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.