PhD projects

PhD projects in Computational biochemistry and Computational Chemistry 

Cellular signalling interactions involved in cancer cell tissue heterogeneity 

These separate projects explore overlapping themes from different perspectives: 

Project 1. Descriptions of the protection mechanisms of pathways with protein-protein interactions in diffuse tumours.

Project 2. Comparisons of cellular pathways involved in chemotherapy treatment failure in tumours. 

Background

These projects start with analyses of transcription data to uncover underlying gene expression patterns in diffuse cancers. Stratification of patients according to their transcription profiles reveals their survival characteristics, related in part, due to the surrounding tissue heterogeneity found in biopsies. Tumour microenvironments are central to early cancer stem cells, providing  a protective immunosuppressive environment involving tumour cell metabolic reprogramming. 

Network analysis of transcription data provides a picture of the coordinated gene expression in cancer cells and their microenvironment.  Network motif identification reveals functional units of co-expressed proteins involved in intercellular signalling between neighbouring cells. Mapping the functional units is important, highlighting protein-protein interactions in signalling. This is the basis of  pathway and target discovery. By combining expression data from patient studies, more cellular responses can be revealed. The most critical functional units are candidate pathways for targeted therapies, helping to promote more effective immunological responses.  

Tight junctions and glycosylated interfaces between neighbouring cells contribute to a protective harbour for cancer stem cells, resulting in elusive cell receptor-binding sites. One hypothesis is that young cancer cells are untouchable and a radius of immunosuppression resists apoptotic signals initiated by macrophages. Homeostatic pathways are reprogrammed and evolve during cancer cell proliferation, contributing to an insensitivity to endotoxins and cytokines. Proliferated cancer cells can resist  being challenged immunologically and  are robust to external therapies (called acquired drug resistance). 

References
Hanahan, D., Hallmarks of Cancer: New Dimensions Cancer Discovery 12 (January), 31–46. (2022)  https://doi.org/10.1158/2159-8290.CD-21-1059
General Background
Vasan, N., Baselga, J. & Hyman, D.M. A view on drug resistance in cancer. Nature 575, 299–309 (2019). https://doi.org/10.1038/s41586-019-1730-1
Drug resistance background
Haider, T., Pandey, V., Banjare, N., Gupta, P. N., & Vandana Soni, V., Drug resistance in cancer: mechanisms and tackling strategies. Pharmacol Rep 72(5), 1125-1151.(2020)  https://doi.org/10.1007/s43440-020-00138-7.
Drug resistance Background
Hsu, N.S.,  En Hui, E.W.,  Liu, M.,  Wu, D., Hughes, T.A., & Smith, J. Revealing nuclear receptor hub modules from Basal-like breast cancer expression networks  PLoS One 23 (June),  16(6): e0252901 (2021). https://doi.org/10.1371/journal.pone.0252901 
Computational systems biology
Thomas, D. , Rathinavel, A.K. &  Radhakrishnan P Altered glycosylation in cancer: A promising target for biomarkers and therapeutics Biochim Biophys Acta Rev Cancer. 1875(1):188464. (2021) PMID: 33157161  PMCID: PMC7855613   https://doi.org/10.1016/j.bbcan.2020.188464
Background
SMITH: Spatially Constrained Stochastic Model for Simulation of Intra-Tumour Heterogeneity BioRxiv Now published in Bioinformatics https://doi.org/10.1093/bioinformatics/btad102
Computational biology
S. E. Thomas, V.  Mendes, S. Y. Kim, S. Malhotra, B. Ochoa-Montaño, M. Blaszczyk and T. L. Blundell (2017). Structural Biology and the Design of New Therapeutics: From HIV and Cancer to Mycobacterial Infections A Paper Dedicated to John Kendrew J Mol Biology 429, 2677–2693.  https://doi.org/10.1016/j.jmb.2017.06.014
Computational biology and chemistry

Early bird catches the worm!  

We are looking for collegial research students, who are excited to travel to conferences and network with other colleagues widely around the world. A PhD is a professional development training to be a researcher. Researchers work assiduously, often at pace, independently, and under time pressures. 

They are motivated that their contributions to science  no matter how small, translate into an impact, in our case help reduce morbidity.  Researchers have to be critical and their work must be reproducible by others.

Interested in applying? 

Applications will be considered on an on-going basis.  Informal enquiries should be sent to Dr James Smith  j.smith252@leeds.ac.uk first. There is no deadline. Do not rush the preparation of the formal documentation below. 
All applicants are required to submit the following:

• if English is not the first language, applicants must provide evidence they meet the University's minimum English language requirements for post graduate research study (see below). 

• certificates or certified transcripts of all degrees studied, or if in final year of study, full transcripts to date,,

• A well-written and proofread Cover Letter with the following short sections,
  1. a  Personal Statement (~2/3 page) introducing your current background and highlighting previous research project experience, 
  2. an Interest & Motivation statement (~1/3 page) in pursuing the advertised project and career aspirations afterwards,  and
  3. a Research Proposal (2-3 pages) with the project title (from above) describing simple objectives, training required and describing any foreseen issues to be faced in the first year. Candidates are encouraged to suggest a name of a previous Tutor/Lecturer from other Universities who could advise on the proposed project,
  4. evidence of Past Teamwork in Science (~1/2 page), from teaching or demonstrating or supporting junior colleagues,
  5. an example of an extra-curricular activity  as a healthy distraction from the pressure of doing science during working hours, for a work-life balance.
  6. a short summary of Funding information including alternative sources of funding that will be applied for, or a statement confirming  that they are able to pay their own fees and maintenance.

• an up-to-date CV with the names and addresses of Academic or Professional  Referees.

Entry requirements

Applicants to research degree programmes should normally have at least a first class or an upper-second class British/EU BSc(Honours) degree (or equivalent) in an appropriate discipline. For this project, a  Masters' degree or postgraduate research experience, is preferred in an appropriate discipline.  Evidence of a strengths in any of the following: Chemistry, Chemical Biology, Pharmacology, Molecular Pathology or Cell Biology,  Computational Chemistry, Computational Biology, Bioinformatics, Biophysics.

Developing computing skills will be required to assimilate large data. Training will be provided. Candidates should have an interest in learning or have some experience in programming or scripting, typically using Regular Expressions, statistical computing in R, Python or Julia. 

English language requirements

Grammatically correct written English is essential in scientific publishing and science communication. 

The minimum English language entry requirement for research postgraduate research study is an IELTS of 6.5 overall with at least 6.0 in each component (reading, writing, listening and speaking) or equivalent. The test must be dated within two years of the start date of the course in order to be valid.

Evidence of spoken scientific English is essential. An interest in critical and constructive proof-reading is essential. Evidence of authorship of a scientific report in English is essential. Co-authorship on a publication is preferable but not essential.

Selection

In line with the University's policies, Shortlisted Candidates will be interviewed. They will also be selected on their ability to communicate 

i) a short presentation on previous research experience, and

ii) describing ideas and thoughts about the problem solving described in their Research Proposal (above). 

Highly Recommended before starting  the research project 

The ability to administrate and update a personal Apple Macintosh Macbook (or Pro or Air) used for research work only .

These computers are supported in our Research Groups  and can be purchased second-hand  or as refurbished models up to 5 years old..