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The Development of Bio-Analytical Techniques for the Treatment of Psoriasis and Related Skin Disorders.
[Thesis]. Manchester, UK: The University of Manchester; 2010.
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Abstract
AbstractThe University of ManchesterKatherine Anne Hollywood: June 2010Degree of Doctor of Philosophy in the Faculty of Engineering and Physical SciencesThe Development of Bio-Analytical Techniques for the Treatment of Psoriasis and Related Skin Disorders.In this investigation a number of post-genomic technologies have be applied to study the dermatological disorders of psoriasis and keloid disease. In spite of considerable research focus on these diseases the pathogenesis remains unclear and currently no cure is available however, both diseases are manageable by drug intervention. It is common place that patients who are suffering from skin disorders are diagnosed and the extent of the disease assessed by a dermatologist which may be subjective due to human error. The availability and application of methods to screen patients and quantify the level of disease or response to treatment has obvious benefits in disease management. The work has incorporated a two-pronged approach combining the spectroscopic analysis of excised tissue samples and the phenotypic profiling of a rapidly proliferating cell line in response to drug intervention. The initial analysis of psoriatic skin samples by MALDI-MS provided poor results which remain relatively unexplained; however similar problems have been observed by other research groups. In a complementary approach the HaCaT cell line was exposed to increasing concentrations of three anti-psoriatic drugs namely dithranol, methotrexate and ciclosporin and the cells profiled using both metabolomic and proteomic methods. A number of metabolic pathways were highlighted including glycolysis and the TCA cycle. This has resulted in a selection of potential biomarkers which could be investigated in further work. In a small follow on study a collection of plasma samples from patients undergoing methotrexate treatment were analysed. The level of patient metadata and the number of samples was relatively limiting however, a subset of metabolites were significantly altered between responders and non-responders and with further validation could be potential biomarkers of successful treatment. The analysis of excised keloid samples was conducted using FT-IR microspectroscopy where it was possible to successfully discriminate between keloid and normal tissue. The use of imaging FTIR illustrated the complex cellular composition within a keloid scar, with increased lipid, amide and phosphate levels being observed. These measurable variations could, in the future, be incorporated into surgical procedures to allow targeted excision ensuring all keloid areas are removed. Finally a SERS-based analysis was conducted to investigate the possibility of probing dynamic enzymatic processes. This was successful and with the use of varying reporter molecules could be a beneficial tool for the analysis of metabolic processes.This project has successfully used a number of bio-analytical techniques to investigate dermatological problems. While the ultimate goal would be the application of a single analytical technique to provide answers to biological questions, it has been found that a number of complimentary techniques and statistical data handling approaches can provide a valuable insight into the problems posed.