Role of primary cilium in morphogen signalling modulation by Transforming Growth Factor-beta (TGF-beta) and its involvement in tissue fibrosis and abe

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...rrant wound healingThis project will investigate the molecular basis of tissue fibrosis, at the epigenetic, molecular and cellular level. Tissue fibrosis is the result of tissue regeneration 'gone bad', and is accompanied by the activation of tissue resident fibroblasts to secrete large amounts of collagen to the extracellular matrix that change the microenvironment for the tissue-specific cell types, impairing the function of the tissue.This project will study the molecular basis of changes in signal transduction that occur in fibroblasts when they undergo activation, using Scleroderma as a model of fibrosis. Scleroderma is an autoimmune disorder of unknown aetiology that results in widespread fibroblast activation, commonly diagnosed in the skin, but in severe cases extended to internal organs like lungs and heart. Key differences in signalling of the morphogens Shh, Wnt, and TGF-B have been found in fibroblasts isolated from patients or healthy controls, and a striking distinctive shortening of the primary cilium in the diseased cells has been observed. The primary cilium is like a cellular antenna where several key receptors localise, and subtle changes in its morphology have been known to cause a large range of defects and disorders. This project will investigate if the morphological change in the primary cilium of fibrotic fibroblasts is the cause of the defective response to important signalling molecules that maintain the normal anatomy and function of the skin, and study if the short cilia are the result of epigenetic changes that persist in the cell population or if they are easily reversible and amenable to therapeutic interventions. The project will be carried out partly in the Faculty of Biological Sciences in the main campus of the University of Leeds, working with Dr. Riobo-Del Galdo's group in signal transduction, protein purification, molecular biology, high resolution imaging and biochemical assays, and partly in Dr. Del Galdo's lab located in the St. James' University Hospital campus, handling patient biopsies, isolating of primary cells, and engineering in vitro multi-layered "skin equivalents" to investigate the effect of the primary cilium and morphogen signalling on epidermal growth and angiogenesis assays.