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Title: Identification of novel targets in fibrosis
Author: Verneau, Johanna
ISNI:       0000 0004 7232 6835
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2018
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Fibrosis is a major pathological feature of many chronic diseases characterised by activation of fibroblasts, accumulation of extracellular matrix (ECM) and persistent inflammation which can lead to impaired organ function and ultimately, to organ failure. To date, there is no effective treatment to delay, halt or reverse fibrosis. Therefore, there is an urgent unmet need for a better understanding of the mechanisms leading to pathological fibrosis to identify potential new targets and biomarkers. The aims of this project are to identify genes altered in fibrosis in 3 major organs (lung, skin and kidney); to shortlist relevant genes using key criteria; and, to explore in vitro and in vivo the function of selected genes under normal and fibrotic conditions. An extensive in silico analysis using published literature and microarray datasets from 1988 to 2015 was performed. Hundreds of genes were identified with a wide variety of functions. Among them, 91 were common for pulmonary, dermal and renal fibrosis while 180 were specific genes altered in lung (60 genes), skin (60 genes) and kidney fibrosis (60 genes). A subset of 12 genes was selected using key criteria including potential drugability and the availability of reagents for further study. Expression of the 12 short-listed genes was explored in human fibrotic fibroblasts and tissues and their function was examined in vitro and in vivo. Data showed that 3 of the 12 selected genes were significantly associated with fibrotic fibroblasts and tissues: Tetraspanin 13 (TSPAN13), Hyaluronan synthase 2 (HAS2) and Cell migration-inducing protein, hyaluronan binding (CEMIP). TSPAN13 has not previously been explored in fibrotic diseases. Here, TSPAN13 was found up-regulated in fibrosis and appears to be a potent pro-fibrogenic molecule with critical functional activities relevant to fibrosis. HAS2 and CEMIP, both genes involved in the hyaluronic acid (HA) pathway, were up- and down-regulated in fibrotic settings respectively. These data showed that TSPAN13, HAS2 and CEMIP are significantly regulated in fibrotic settings suggesting an important role in fibrosis. Therapeutic antibodies are being developed against the two up-regulated targets, TSPAN13 and HAS2, as potential anti-fibrotic therapies.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available