About the Project
Complexity in the human proteome is brought about through the alternative splicing of single pre-mRNAs to produce multiple isoforms that code for different protein variants. This alternative splicing is highly regulated during development and in response to cellular stimuli in specific cell types. It is now clear that manipulation of the splicing process by drugs is a promising avenue for the development of new therapeutic agents. We have identified a number of small molecules that influence splicing and may be useful therapeutic agents, in particular for treatment of cancer. It is, however, not clear how these drugs work to affect splicing as we have little understanding of how drugs influence the splicing process on the molecular and global transcriptome level. Knowing how these molecules specifically affect splicing will allow more rational design of drugs that specifically target certain splicing programmes as well as prevent unintentional effects on splicing, for example, leading to toxic outcomes. In this basic research proposal, we aim to determine the mechanisms of how these molecules influence the pre-mRNA splicing machinery and the global splicing program in different cancer cell types. In addition, the project will use both chemical and modelling approaches to probe the structure-activity relationship of these molecules to improve their ability to influence splicing and to control cancer cell growth. Addressing these objectives will ultimately have a significant impact on human health with the increased clinical, economic and societal benefits of providing new therapeutic entities with improved efficacy and side effect profiles.
http://www.manchester.ac.uk/research/rokeefe/
Funding Notes
This project is to be funded under the BBSRC Doctoral Training Programme. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the BBSRC DTP website www.manchester.ac.uk/bbsrcdtpstudentships
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.
References
Jenkinson, EM, et al. O’Keefe, R.T. and Crow, Y.J. (2016). Mutations in SNORD118 cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts. Nature Genetics. 48:1185-92
Wieczorek, D., Newman,W.G., et. al. O’Keefe, R.T., Meitinger, T., John Burn, J., Lüdecke, H-J., Strom, T.M. (2014) Compound Heterozygosity of Low-Frequency Promoter Deletions and Rare Loss-of-Function Mutations
in TXNL4A Causes Burn-McKeown Syndrome. American Journal of Human Genetics. 95(6):698-707.
Hogg, R., Alves de Almeida, R., Ruckshanthi, J.P.D., and O’Keefe, R.T. (2014). Remodelling of U2-U6 snRNA helix I during pre-mRNA splicing by Prp16 and the nineteen complex protein Cwc2. Nucleic Acids Research. 42:8008-23.
Christou, S., Edwards, A.C., Pritchard, R.G., Quayle, P., Song, Y., Stratford, I.J., Williams, K.F., Whitehead, R.C. (2016). Synthesis of hybrid natural product analogues with anti-tumour properties. Tetrahedron. 72(35): 5433-5443.
Ghattas, M. A., Mansour, R. A., Atatreh, N., Bryce, R. A. (2016) Analysis of enoyl acyl carrier protein reductase structure and interactions yield an efficient virtual screening approach and suggest a potential allosteric site. Chem. Biol. Drug Des. 87:131–142
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