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

Lead Research Organisation: University of Liverpool
Department Name: Institute of Ageing and Chronic Disease

Abstract

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.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M011186/1 01/10/2015 30/09/2023
1945098 Studentship BB/M011186/1 01/10/2017 30/09/2021 Emily Johnson
 
Description The project aimed to create computational models to describe how type I collagen, the most abundant protein in the human body, can become dysregulated, and how this dysregulation can lead to imbalances in type I collagen synthesis-over-production, under-production, or production of an abnormal form of type I collagen. The abnormal form is thought to be weaker and is implicated in several diseases. So far, during my project I have identified several key areas of regulation to study, taking several of these further to model mathematically.


Transcriptional/post-transcriptional regulation:

A model was created describing how a cytoskeletal protein, vimentin, can stabilise type I collagen mRNAs. The model demonstrated vimentin availability was a limiting factor in stabilisation. This may be relevant in processes such as wound healing and fibrosis where vimentin is up-regulated and may lead to increased type I collagen production.

Alternative polyadenylation results in the production of shoter isoforms of certain genes. RNA decay experiments have revealed that the shorter forms of type I collagen mRNAs have longer half-lives. This is to be expected as shorter mRNA isoforms lack the binding sites for elements that could otherwise degrade them. Preliminary results also suggest vitamin C may act to stabilise some collagen mRNAs. This information will be used as a basis for another model of type I collagen mRNA regulation, featuring the interplay between RNA binding proteins and miRNAs. The models will simulate how the ratios of different type I collagen mRNAs will change in response to certain conditions and how this could lead to production of the abnormal form.

Publically available RNAseq data sets acts to complement this work. These datasets can be analaysed so the ratio of the short:long isoform for each gene in the dataset can be calculated and used as an input for modelling. Datasets of interest have come from different cell types and have included factors such as ageing, wound healing, fibrosis, and cancer. So far they have suggested that production of the shorter isoforms is affected with age and greatly increased in breast cancer. This work was supplemented by a four day training course carried out at the University of Newcastle (an introduction to practical bioinformatics).


Pre-translational/translational regulation:

No key findings associated with this yet, however two models are in progress, studying transport of type I collagen mRNAs to the endoplasmic reticulum for translation and how calcium homeostasis might affect the formation of the abnormal form of type I collagen over the regular form. The first is an ODE model and the second is using a molecular dynamics approach.


Other:
Human skin cells embedded in contracting collagen gels-which simulate the end stages of wound healing-demonstrate an upregulation in pro-apoptotic genes after 12 hrs. A particular pro-apoptotic protein, PDC4, was speculated to be involved in this process too but so far results have been inconclusive. RNA was also extracted from gels with different collagen concentrations to see if gel 'stiffness' would have any effect on type I collagen production. This may be relevant in fibroblast clearance after wound healing and over-production of type I collagen in fibrosis.
Exploitation Route The completed models will be deposited on the BioModels database (https://www.ebi.ac.uk/biomodels-main/) after they've been published. The BioModels database acts as a repository of curated computational models of biological processes. These models can then be integrated into future researcher's models, built upon and refined. Type I collagen post-transcriptional regulation is still poorly characterised so these models may form a basis for further research.

Additionally, computational models can identify key areas of regulation and which aspects of the network would be most amenable to future pharmacological interventions.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology