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More about Giulia

Thesis Title: The Interactome of Transglutaminase 2 in Kidney Fibrosis

I am a PhD student in the School of Science and Technology undertaking research for my thesis entitled The Interactome of Transglutaminase 2 in Kidney Fibrosis. Chronic Kidney Disease (CKD) is a pathologic condition characterised by progressive loss of kidney structure and filtrating function over time, leading to end-stage kidney failure. Currently there is no cure for this disease, and the only treatments for end stage patients are dialysis or organ transplant. The main event associated with the progression of the disease to renal failure is a gradual scarring / fibrosis of the organ.

Kidney fibrosis is characterised by a progressive reduction in renal cell number and function and corresponding accumulation of extracellular matrix (ECM). These events have been associated with an increased extracellular export and activity of the enzyme Transglutaminase-2 (TG2). TG2 is a calcium dependent protein crosslinking enzyme, that catalyses the formation of covalent bonds between proteins, which are highly resistant to proteolysis. Because of this function, an increased extracellular activity of TG2 can determine fibrosis by shifting the extracellular balance to matrix deposition, reducing the proteolytic breakdown.

The correlation between extracellular TG2 and kidney fibrosis has been demonstrated in vivo in models of kidney fibrosis. As the fibrosis progresses, TG2 expression and activity typically increases at the basal membrane of the cells. Specific inhibition of this enzyme has a protective role against fibrosis, both in vivo and in vitro. However, the clinical application of this direct inhibition is almost impossible, as it interferes with other fundamental members of the TG family (e.g. clotting factor FXIIIA) resulting in major side effects. Therefore specific inhibition of TG2 is required and this may be reached by broadening our understating of TG2 export.

The aim of my study is to highlight potential partners that interact with TG2 during its trafficking to the cell surface, to find potential targets to use in order to reduce or abort the enzyme externalisation. For example, recent works have highlighted a novel interaction between TG2 and cell surface Heparan Sulphate Proteoglycans (HSPGs) and the potential implication of this in wound healing and scarring. In particular Syndecan-4 has been pointed as the main receptor for TG2 on the cell surface.

My work entails a variety of approaches, from experiments in renal tubular epithelial cells, manipulated by cell transfection, to production of recombinant proteins as well as bioinformatics analysis of experimental data using Systems Biology approaches. I am also collaborating on other projects, for example applying my bioinformatic and analytical skills in the analysis of proteome data for the research group, and helping new MSc / MRes and PhD students.

Director of Studies
Elisabetta Verderio Edwards

Research Groups / Centres and Projects
Biomedical Life and Health Sciences Research

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