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Title: An investigation of glucocorticold resistance in transplant recipients
Author: Chen, Yan
ISNI:       0000 0001 3538 8357
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2007
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Steroids have been an indispensable immunosuppressive component since they were first introduced to transplantation. However, very few studies have pursued the correlation between individual steroid sensitivities and their transplant outcomes. In this PhD project, we mainly investigated glucocorticoid receptor (GR) and FKBP5, two fundamental molecules in GC signaling pathways, at the levels of gene polymorphism and gene expression. Associations were sought between genetic variations and in vitro steroid responsiveness in PBMC cell culture, as well as graft function after transplantation. Additionally, polymorphisms of several genes on chromosome 6p, Le. VEGF, FKBP5, HLA-DR and TNF-a, were studied for underlying linkage disequilibrium. The data have shown the GR gene haplotype (e.g. GR33388*A-766*C-3·569*A) may be related to steroid sensitivities in normal and transplant populations, although clinical applications for this genotype-phenotype association are still vague. GR3669*A/G has also been shown to be associated with regulation of the production of the hGRp isoform. The dexamethasone (Dex) dosage vs. inhibition curves established in in vitro PBMC proliferation assays have defined individual variations in response to Dex treatment and may provide a feasible laboratory test candidate to predict the cellular steroid sensitivity of tre.'5plant patients who possibly confront inflammatory challenges. In addie. n, the study of transplant patients for their FKBP5 and GR isoform gene expression has shown dramatic changes induced by steroids and/or inflammatory stimulators. The hGR-P isoform stood out from other GR isoforms and provides a new direction in studying regulation of GR isoforms during immune activition. Finally, two putative haplotypes were identified in association with DR52 and DRI on chromosome 6p, and named as 'high inflammatory' and 'low inflammatory' haplotypes respectively. The uncovering of such haplotypes may help to differentiate individuals according to their risk of acute and chronic rejection after transplantation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available