Please use this identifier to cite or link to this item: http://theses.ncl.ac.uk/jspui/handle/10443/1198
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dc.contributor.authorSpielhofer, Julia-
dc.date.accessioned2012-02-08T09:12:39Z-
dc.date.available2012-02-08T09:12:39Z-
dc.date.issued2011-
dc.identifier.urihttp://hdl.handle.net/10443/1198-
dc.descriptionPhD Thesisen_US
dc.description.abstractTransplantation is often the only therapy for end-stage organ failure. Blood-borne leukocytes are guided into the grafts by proinflammatory chemokines. To achieve full functionality, chemokines interact with heparan sulphate (HS) proteoglycans, which are expressed on the majority of all animal cell surfaces, predominantly on the endothelium. Due to the modification, especially sulphation status of HS, chemokine function can be controlled. This study was designed to examine the expression of different HS epitopes during allograft rejection, dynamic changes of HS following experimental inflammation and investigate the regulation of HS biosynthesis, providing new targets for therapeutic intervention. Human renal and hepatic allografts expressed distinct HS epitopes which were indicative for the stage of rejection. In both organs, N-sulphated HS domains were elevated during acute phases of rejection whereas 2-O- and 6-O-sulphation increased significantly during chronic stages. The HS motif investigated could be matched to selective HS ligands based on essential target modifications. Data from transplant tissues was largely confirmed by in vitro studies simulating an inflammatory response employing relevant cell lines and N-deacetylase/N-sulphotransferase (NDST1) transfectants. Investigations of the regulation of HS biosynthesis at the protein level were carried out using tandem affinity purification. It revealed an interaction of NDST1, the key enzyme in HS biosynthesis, and beta tubulin. This interaction could provide an insight into general Golgi localisation and retention of glycosylation enzymes. This study substantiates the strategy of targeting heparan sulphate proteoglycans in inflammation and organ rejection, as distinct changes in HS epitope expression dependent of the stage of rejection were identified. During renal rejection, these specific HS species could be used as a biomarker giving evidence about the progression of the disease. Overall, this could lead to a Abstract novel anti-inflammatory therapy targeting an array of proinflammatory cytokines with less side affects compared to current treatment options.en_US
dc.description.sponsorshipThe EU: The Northern Counties Kidney Research Fund:en_US
dc.language.isoenen_US
dc.publisherNewcastle Universityen_US
dc.titleRole of heparan sulphate in inflammation and allograft rejectionen_US
dc.typeThesisen_US
Appears in Collections:Institute of Cellular Medicine

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