Developing NMR Methods to Characterise Cell Signalling Pathways for Novel Drug Discovery

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Cells detect and respond to the local mechanical properties of their environment. Changes in the viscosity and stiffness of a cell's surroundings cause significant changes in cell function and metabolism, but the mechanisms for these cell changes are still poorly understood. These effects are however very important; cancer cell invasion of surrounding tissue is promoted with increasing tissue stiffness, for instance. One of the blocks in research in this area is the paucity of methods to measure local changes in stiffness and viscosity around cells. Alongside this is the need for methods to assess how the structure and dynamics of extracellular matrix molecules that signal to cells are affected by changes in local stiffness/ viscosity, in order to understand the molecular effect of mechanical property changes on cell signalling from the extracellular environment. This project will first develop solution-state, gel-state and solid-state NMR methods to measure changes in local viscosity and stiffness around cells. We will then progress to develop an NMR toolkit to understand how the dynamics and conformations of extracellular matrix molecules correlate with the matrix viscosity and stiffness. Finally, we will use NMR methods and optical imaging to understand of extracellular matrix molecues interface with cells to generate cell signaling. Drawing together the results from the whole project will lead to new hypotheses about how cells sense their environment. Overall, the project will provide physical methods to enhance research at the interface between chemistry and biology.