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Method development approaches towards the identification and validation of disease-related protein targets

Nobre da Cruz, IM; (2014) Method development approaches towards the identification and validation of disease-related protein targets. Doctoral thesis , UCL (University College London). Green open access

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Abstract

The search for novel biomarkers and therapeutic targets is a continuous process in the fight against disease. In this project, target identification and validation approaches were used towards the discovery of protein targets related to distinct, but equally relevant diseases. The first approach involved the use of proteomics to identify protein targets in infertility. An affinity-enrichment proteomic method was developed and successfully applied to the identification of protein targets of a clinically utilised compound, which is known to cause reversible, dose-dependent male infertility in certain mouse strains. The second approach demonstrated the versatility of proteomics in an attempt to answer a completely different question. In this study, it was applied to the discovery of protein targets of chemoresistance in ovarian cancer, using human ovarian cancer cell lines and tissue biopsies. Once again, this method was successful in identifying some very promising un-regulated protein targets and pathways involved in cancer resistance. Finally, a more assay development orientated approach aimed for the functional characterisation of Hsp90 targeted compounds. The combined use of a native gel binding assay and an Hsp90 ATPase assay proved to be a convenient and robust method to characterise Hsp90 inhibitors and will aid the development of Hsp90 targeted anti-cancer drugs. In summary, the work undertaken confirmed the recognised advantages of proteomics in the comparative study of un-regulated proteins connected to disease. It equally showed how two distinct techniques could be used in synergy to accomplish more valuable answers, in the screening of inhibitors of a known protein target.

Type: Thesis (Doctoral)
Title: Method development approaches towards the identification and validation of disease-related protein targets
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
URI: https://discovery.ucl.ac.uk/id/eprint/1433951
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