Systems modelling age-related changes in the maintenance of dermal extra-cellular matrix: mechanisms and interventions.

Lead Research Organisation: Newcastle University
Department Name: Biosciences Institute

Abstract

Age-related changes to the structure of the skin such as thinning, wrinkling and loss in flexibility are the result of changes in the regulation and composition of the dermal extra-cellular matrix (ECM). With age processes that degrade the ECM tend to dominate over regenerative processes. The consequences are the visible changes we all know together with increased incidence of conditions such as psoriasis, fibrosis, melanoma and impaired wound healing. Advanced anti-ageing skin-care products that target the causal mechanisms underlying these changes are a multi-billion pound industry which is forecast to increase over the coming decades. However much remains unknown about these mechanisms, and an in depth understanding of the processes involved in the maintenance of the ECM will provide better quality products and - perhaps more importantly - further our understanding of the skin ageing process itself.
The use of animals in skincare product development is widespread but is not necessarily very informative due to fundamental differences in biology with humans. Animal testing in cosmetics sold in the UK was first banned for tests carried out in the UK in 1998, EU in 2009 and extended to all countries in 2013. However, many animals, laboratory mice in particular, are routinely used in the basic research leading to identification of novel products for skin healthcare. Here, we aim to use a systems biology approach integrating in-silico discovery and in-vitro validation to offer a powerful alternative to animal experimentation. We will use this approach to generate computer models of age-related changes in the maintenance of ECM in the human dermis and use them to identify intervention strategies to counter undesirable changes.
Our computational models will be informed with data generated from human dermal cells, thereby avoiding focus on processes that may only be relevant in animal models. Once established the computer models will be used to explore treatment strategies and in more complex combinations that can be carried out solely in laboratory experiments. Those treatments that look promising will be tested in our in-vitro system which we have developed to behave very much like human skin. Our in-vitro dermal model allow us close control over which cells are grown within the tissue and how we can study them. We will use our system to help streamline product development for industry. An additional outcome will be a central computational resource where our data and models will be kept together and a software interface to allow others to interact with the models.

Technical Summary

Overall, we will measure in-vitro and model in-silico the short-term biochemical network dynamics of extra cellular matrix maintenance (ECM) in populations of young, old and senescent dermal fibroblasts. We have shown in previous work that differences in network dynamics are highly informative and provide a means to identify parts of the network that could be targeted to restore healthy function. The work will be first carried out in 2D culture of human dermal fibroblasts then extended to a novel 3D in-vitro system which we have established and validation as a reliable surrogate for the human dermis. Intervention strategies will be explored in the computational model and subsequently tested in-vitro. The work will involve: generation of high throughput time series data; development and application of bioinformatics workflows to analyse the data and establish networks of molecular interactions governing the maintenance of ECM; building, calibration and validation of dynamic computational model(s) in vitro; use of the model(s) to identify intervention strategies to modify network behaviour; testing of molecules in vitro that could be used in potential treatments to improve skin healthcare.

Publications

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