Targeting myofibroblast mechanotransduction to prevent pulmonary fibrosis

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Idiopathic pulmonary fibrosis (IPF) is a long-term chest condition that is characterised by fibrosis (scarring) of the lungs. This scarring reduces the ability of the lungs to take in oxygen, which causes a person to feel breathless. It is not clear why some people develop IPF, but people with IPF often progress to death quickly and there is no cure. This makes IPF an important disease to research. The main feature of lung scarring is that the lungs become small and stiff due to the abnormally high activity of cells that make scar tissue. These cells produce proteins that make the lungs stiff, such as collagen, and contract, making the lungs small. Previous studies have shown that the lung scarring in IPF begins in the areas of the lung that are being stretched the most. Research has also shown that when cells grow in stiff surroundings, like that within scarred lung, they become even more active and produce more scar tissue. We also know that lung injury causes the release of a chemical called lysophosphatidic acid (LPA), which causes many events that lead to lung scarring. G proteins are a group of proteins that are "switched on" by sensing molecules on the cell surface (G protein-coupled receptors, GPCRs) and pass on this information by activating other proteins inside the cell. When this signal reaches the cell nucleus, the "control centre" of the cell, it controls which genes are switched on and which proteins are made. We know that two families of G-protein (Ga12/13 family and Gaq/11 family) pass on signals that lead to lung scarring. Both groups of G proteins can be switched on by mechanical forces, although my early experiments suggest the mechanical forces transmitted by these two groups are different. My early results suggest that cells grown in "stiff" surroundings sense signals which involve the Ga12/13 family whereas cell which are stretched (as occurs during breathing) pass signals through the Gaq/11 family, leading to different cellular responses which both promote scarring.The aim of this project is to find out precisely how the Ga12/13 and Gaq/11 families sense different types of mechanical signals (stretch and stiffness of surroundings) and cell injury signals, and how these lead to lung scarring. We will compare how the Ga12/13 and Gaq/11 protein families react to injury, cell stretch and changes in matrix stiffness with cells that don't have Ga12/13 or Gaq/11. I will also look into whether cells from people with and without IPF have different amounts of Ga12/13 and Gaq/11 activity. In addition, I will use a model of pulmonary fibrosis where the the scar producing cells do not have the Ga12/13 or Gaq/11 family of proteins and measure how the absence of these proteins affects the development of fibrosis in the lung. To measure scarring in these experiments, I will measure the expression of important proteins and genes that are involved in lung scarring, including collagen, and molecules that make these cells more active (scar forming). I will also measure both the stiffness of the lung and the scar tissue made by the cells grown for these experiments. This is a method of measuring the level of fibrosis not often used in this kind of research, making this project unique. From these experiments, I hope to learn more about the reasons behind how and why IPF develops. I will use the results to draw a map starting with the signals from the cell's surroundings, such as stretch and stiffness, through the G protein families, to the production of the substances that may cause lung scarring. By showing how these differ in scarred lung compared with healthy tissue, I hope to find out why IPF develops. The molecules or proteins that I find to be important for the development of IPF may also be good targets for new treatments. Therefore, this project will increase what we know about why IPF develops, and may help us to find a cure for IPF.