Hyaluronan (HA) assembly and its Role in Bone Morphogenic Protein-7 Driven Antagonism of Renal Fibrosis

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Organ failure resulting from fibrosis is the predominant cause of chronic diseases in our population including kidney disease, liver disease, lung and heart disease. However no treatments exist that can halt or reverse fibrosis and prevent organ damage. This research aims to identify targets that can potentially alleviate or reverse fibrosis, with the aim of developing new therapies to prevent end-organndamage in at-risk patients.Myofibroblast are the principle fibrosis-producing cells. They are produced by the circulating factor TGF-beta-1 through transformation of epithelial cells and fibroblasts. BMP7 is another circulating factor, which opposes TGF-beta-1-driven fibrosis. However, neither direct blocking of TGF-beta-1, nor treatment with BMP7 are viable therapies as they cause significant side effects. Thus we need to further study these two circulating factors to identify more targetted therapy with less side effects. Our department has previously shown that TGF-beta-1-driven formation of myofibroblasts is dependent on how cells make and assemble a third molecule, Hyaluronan (HA). We also know that BMP7 can assemble HA differently to TGF-beta-1. Our aim is to carry out detailed studies to determine the effects of BMP-7 on how fibroblasts/epithelial cells generate, assemble and handle HA; thus allowing us to differentiate between good and bad HA. This will allow us to prevent formation of myofibroblasts, thus enabling us to identify therapies that can prevent or reverse fibrosis in at risk patients.