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Computational design and experimental validation of peptide modulators of RAS signalling pathway


Leeds CRUK Cancer Centre

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Dr N Fernandez-Fuentes , Prof T Rabbitts No more applications being accepted Competition Funded PhD Project (European/UK Students Only)

About the Project

Critical cellular processes such cell growth and division are regulated by a set of orchestrated and finely regulated specific protein-protein interactions that activate or inactivate signalling pathways. RAS proteins act as upstream molecular switches and play a key role in signal transduction. RAS was firstly isolated from a human bladder carcinoma cell line(Shih and Weinberg 1982). Since then, the RAS family have been intensively studied and the data shows that the frequency of RAS mutations is among the highest for any gene in human cancers(Reuter et al. 2000). The reason lies in the fact that RAS is a central hub in a number of signalling pathways that includes proliferation and gene transcription. When RAS is constitutively activated because a mutation(s) the related signal transduction pathways may become also activated, degenerating, eventually, into carcinogenic state. Therefore, specifically blocking the interaction of RAS with any of its partners arises as an important avenue to fight cancer.

The overall goal of the project is the isolation of peptide modulators of RAS signalling pathway. The project encompass with two main tasks: firstly, computational design of peptides; and secondly, experimental validation of the predictions. The computational design of peptide modulators will be carried out using “in house” developed software as well as common tools used in protein design. The second part of the project would be the experimental validation (in vitro) of the predictions, i.e. whether peptides would bind to RAS and block interactions with partners. To that end, the RAS-AntiRAS antibody protein complex (Tanaka et al. 2007) will be used. On a first approach, SPR assays will be used to assess the binding of peptides to RAS. Further characterization would include NMR data, pull-down, and competition assays among other experimental tools.

The candidate will develop his/her research tasks in both a computer-based (dry-lab) and experimental lab (wet-lab). Thus, it will suit a candidate willing to work both with computers and in an experimental lab setting. Although desirable, programming skills are not essential, however training will be provided as required.

References

Reuter, C. W., M. A. Morgan, et al. (2000). "Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malignancies?" Blood 96(5): 1655-69.

Tanaka, T., R. L. Williams, et al. (2007). "Tumour prevention by a single antibody domain targeting the interaction of signal transduction proteins with RAS." EMBO J 26(13): 3250-9.

Shih, C. and R. A. Weinberg (1982). "Isolation of a transforming sequence from a human bladder carcinoma cell line." Cell 29(1): 161-9.



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