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(BBSRC DTP) Developing small molecule inhibitors of pre-mRNA splicing into effective therapies for cancer


Faculty of Biology, Medicine and Health

Manchester United Kingdom Biochemistry Cancer Biology Computational Chemistry Genetics Molecular Biology Pharmaceutical Chemistry Pharmacy Synthetic Chemistry

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 for cancer. We have identified a number of small molecules that influence splicing and may be useful therapeutic agents for 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 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/

Entry Requirements:
Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

UK applicants interested in this project should make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/).

If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.

Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the BBSRC DTP website http://www.manchester.ac.uk/bbsrcdtpstudentships

Funding Notes

Funding will cover UK tuition fees/stipend only. The University of Manchester aims to support the most outstanding applicants from outside the UK. We are able to offer a limited number of scholarships that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website View Website

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