Sajjad, Usman (2012) Investigating the Pathology of Endometriosis through the use of Bioinformatics. Masters thesis, University of Liverpool.
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BACKGROUND Endometriosis is a common gynecological disease with unknown pathogenesis. There is a lack of clear understanding towards the pathogenesis and etiology of the disease, and as a result, a deficiency of effective treatment methods. Past theories and approaches have ignored interactions between genes on cellular level and how processes such as the immune system genetically can influence the development of the disease. HYPOTHESIS Bioinformatics, an evolving form of computational technology, can be used to systematically and methodically collate available information on gene expression and relevant transcription factors with aim of identifying the key players in the disease process. METHODS Genomic/Proteomic information was inputted into software programs such as Ingenuity IPA, GenEvestigator and Opossum. The software was able to produce network maps of biological pathways and meta-analysis plots of genes/proteins differentially expressed during endometriosis. Common regulatory transcription factors were subsequently identified for these up-regulated genes. Immunohistochemistry (IHC) work was conducted to validate and analyze the expressional pattern of FOXD3 in endometrial samples of 20 patients (n=20). The expression in 10 normal fertile control endometrial samples (n=10) was compared to 10 endometrial samples from women with active peritoneal endometriosis at two different stages of the menstrual cycle (proliferative phase and window of implantation). The same sets of samples were used to compare any changes in expression of Androgen receptors (AR) and Progesterone receptors (PR), based on findings we obtained from our bioinformatics work. RESULTS We found FOXD3 to be the most common transcription involved in endometriosis, controlling 16 out of 38 up-regulated genes. SPP1, PTGS2, IL-8, StAR and CXCR4 were found to be strongly up regulated in patients with endometriosis. The same pattern of up-regulation genes was seen in gastric cancer. AR and PR were seen to interact centrally with other genes/proteins in the Ingenuity IPA network map. From the IHC work, we found FOXD3 to be expressed in the luminal epithelium and glandular compartments of the normal proliferative endometrium. In patients with endometriosis, there was an increase in expression of FOXD3 in the luminal epithelium and glands of secretory endometrium. There was no significant difference between the expressional pattern of AR and PR in the endometrium of normal fertile control women and endometriosis patients. DISCUSSION We concluded FOXD3 to be a key player in the pathogenesis of endometriosis. The transcription factor was able to control up-regulated genes on a cellular level in various pathological processes, which contribute to the development of endometriosis. We propose future work is needed to extend the investigative measures of FOXD3 in the pathogenesis of endometriosis and elucidate how it can be a therapeutic target for treatment purposes in a clinical setting.
|Item Type:||Thesis (Masters)|
|Uncontrolled Keywords:||endometriosis, bioinformatics, obstretics and gynaecology, dysmenorrhoea, FOXD3|
|Departments, Research Centres and Related Units:||Academic Faculties, Institutes and Research Centres > Faculty of Medicine > School of Reproductive & Developmental Medicine|
|Deposited On:||07 Aug 2012 12:08|
|Last Modified:||07 Aug 2012 12:08|
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