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Identification and functional characterisation of BRIT1/MCPH1 synthetic lethal genes to treat breast and ovarian cancer


Project Description

Women who have undergone surgery for breast and ovarian cancer often have additional chemotherapy to kill residual cancer cells and prevent recurrence. Unfortunately, 30-40% of these patients’ tumour cells are resistant to these treatments.

We have identified reduced expression of BRIT1/MCPH1, a DNA damage response gene in a third of ovarian and breast cancer patients. These reductions were associated with increasing tumour grade and poor survival1-2. Recently we have performed two complementary large-scale druggable genome siRNA screens to identify BRIT1/MCPH1 synthetic lethal (SL) genes. SL genes are when mutations in one gene alone has no effect on cell viability, however, mutation in both genes leads to cell death. Thus, targeting a SL gene in a cancer with BRIT1/MCPH1 mutations should selectively kill the cancer cells but not normal cells.

Analysis of cell viability data from the two siRNA screens, one with BRIT1/MCPH1 knockdown the other without has been performed identifying a number of interesting candidate genes (including other DNA repair genes) which preferentially kill BRIT1/MCPH1 deficient cells. The top SL genes will be selected based on functional relevance and the commercial availability of chemotherapeutic drugs and/or small molecule inhibitors to these targets. Four individual, deconvoluted siRNAs will be used to validate potential SL hits. Functional studies will be performed to investigate the mechanism causing SL in BRIT1/MCPH1 deficient cells.

Potential biomarkers much as BRIT1/MCPH1 will enable us to identify new chemotherapeutic approaches to treat cancer patients that are resistant to current treatments.

Environment:
The student will be based in the Leeds Institute of Biomedical and Clinical Sciences (LIBACS), School of Medicine, University Of Leeds. This project will provide research training in a range of techniques including siRNA gene knockdown, cell culture, RNA extraction, pathway analysis, Real time PCR, immunofluorescence, western blotting, live cell imaging, DNA repair assays and drug cytoxicity assays.

Eligibility:
This project is available immediately to both Home/EU rate applicants and International applicants who are able to self-fund their studies. Students must be able to provide the appropriate level of fees based on their fee status plus laboratory consumables costs per year. This is in addition to the provision of personal living expenses.

You should hold a first degree equivalent to at least a UK upper second class honours degree in a relevant subject.

Candidate whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study, the Faculty minimum requirements are:

• British Council IELTS - score of 6.5 overall, with no element less than 6.0
• TOEFL iBT - overall score of 92 with the listening and reading element no less than 21, writing element no less than 22 and the speaking element no less than 23.

Applicants with sufficient funding must still undergo formal interview prior to acceptance in order to demonstrate scientific aptitude and English language capability.

How to apply
Applications can be made at any time. To formal apply for this project applicants should complete a Faculty Application form using the link below https://medicinehealth.leeds.ac.uk/downloads/download/78/fmh_scholarship_application_form_2018_2019 and send this alongside a full academic CV, degree certificates and transcripts (or marks so far if still studying) to the Faculty Graduate School at

We also require 2 academic references to support your application. Please ask your referees to send these references on your behalf, directly to

Any queries regarding the application process should be directed to .

Potential applicants are welcome to contact Dr. Sandra Bell at with informal enquiries about this research project.

Funding Notes

This project is available for self funded applicants only

References

1. Richardson J, Shaaban AM, Kamal M, Alisary R, Ellis I, Speirs V, Green A & Bell SM (2011) Microcephalin is a novel prognostic marker in breast cancer associated with BRCA1 inactivation. Breast Cancer Res Treat, 127(3):639-48.
2. Alsiary R, Brüning-Richardson A, Bond J, Morrison EE, Wilkinson N & Bell SM (2014) Deregulated microcephalin and ASPM expression in ovarian epithelial cancers. PLoS ONE 15;9(5):e97059.

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