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Molecular modelling of interactions between growth factors and proteoglycans with implications for the pharmacological manipulation of tissue regeneration

Primary Supervisor: Professor Michael ChappellLink opens in a new window, School of Engineering

Secondary supervisor: Professor Ann Logan

PhD project title: Molecular modelling of interactions between growth factors and proteoglycans with implications for the pharmacological manipulation of tissue regeneration

University of Registration: University of Warwick

Project outline:

There is an unmet clinical need for new classes of multi-modal drugs that can invoke and enhance the natural repair and regeneration capabilities of tissues compromised by degenerative conditions. Understanding and predicting the molecular basis of dynamic interactions between key molecules controlling tissue repair is fundamental to the exploitation of regenerative biology for societal impact. This project seeks to develop and test mathematical models that can successfully describe and predict the dynamic interaction of the growth factors responsible for tissue regeneration and elements of the extracellular matrix that regulate their bioactivity. The project will initially focus on developing a deep understanding of the chemistry underpinning the relevant molecular interactions and then using knowledge of prototypic growth factor-matrix interactions to develop mathematical models that can predict the key molecular elements in the interacting partners that regulate the intracellular signalling pathways that initiate regenerative cellular responses. Furthermore, the project will explore the potential utility of such models for the development of drug mimetics capable of modulating growth factor activity that would be useful for enhancing tissue repair and regeneration.

The methods employed would include chemical/pharmacological analyses, dynamic mathematical modelling, cell culture, biochemical analyses, etc.

Reference:

  1. Moussa et a., Sci Rep 2019,9(1):164

BBSRC Strategic Research Priority: Integrated Understanding of Health:Pharmaceuticals

Techniques that will be undertaken during the project:

  • Pharmacological analyses of growth factor-proteoglycan interactions derived from first principles of their chemistry, including nuclear magnetic resonance (NMR) to study real-time dynamics of the molecular interactions.
  • Mathematical modelling of the dynamics of molecular interactions using the software tool SimBiology based on the simulation of parameterised nonlinear Ordinary Differential Equations (ODEs), derived from fundamental mass-balance and mass-action principles.
  • Culture of relevant cells to compare the dynamics and intracellular signalling predictive accuracy of the modelled molecular interactions with cellular reality.

Contact: Professor Michael ChappellLink opens in a new window, University of Warwick