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Studentships

 

AstraZeneca/Pharmacology 4-year PhD studentships

Applications are invited for 4-year PhD studentships funded by AstraZeneca and the Department of Pharmacology. The students will be working on collaborative projects co-led by departmental supervisors and AstraZeneca scientists. Apart from carrying out their research, in their first year, the students will have compulsory training in: 1) Statistics, 2) Analysis of Biological Data and 3) Systems Training in Maths, Informatics, Statistics and Computation Biology (SysMIC). The students will join a vibrant research community of PhD students and scientists working on various research themes such as; Cell Signalling, Cancer and Infectious Diseases, Macromolecular Structure, Neuropharmacology and Vascular Pharmacology.

Candidates

We are looking for highly motivated, enthusiastic individuals, capable of thinking and working independently. Applicants should have or shortly expect to obtain a minimum of a UK II.i Honours Degree (or equivalent) in Pharmacology or a related subject including Cellular or Molecular Biology and Biochemistry. Competition is intense and successful applicants are expected to demonstrate high academic achievements. These positions are open to UK citizens or EU students who meet the UK residency requirements (home fees) or are able to augment the funds to cover the extra costs associated with international student fees.

Funding

Full funding covering the University Composition Fee and Maintenance (currently £17,000 pa), is provided for up to 4 years, with effect from 1 October 2021. A maximum of four studentships will be awarded in this application round.

 

Projects available;

1)    Neuroimmune interactions in visceral pain

Supervisors: Dr David Bulmer  / Dr Ewan St John Smith (Pharmacology)

Project summary

Chronic pain is a leading cause of morbidity in patients with inflammatory diseases such as ulcerative colitis and rheumatoid arthritis. In these conditions pain no longer serves a protective role, but instead causes significant disability and psychological stress, which often persists in periods of remission.

The pathophysiological changes that give rise to the development of chronic pain during active inflammatory disease, and its persistence through remission, are complex and occur across multiple points in the pain pathway from body to mind. Research in the Bulmer and Smith Labs is directed towards understanding the precipitating events in this process. Their work applies multiomic and functional approaches to disease tissues and sensory neurones, including RNA sequencing, electrophysiological recordings and live cell imaging in human and mouse.

This studentship will seek to explore the role of the IL-23/IL-17 signalling pathway in bidirectional communication between visceral nociceptors and innate lymphoid cells in colitis, and its contribution to the development of chronic pain. The project will involve extensive collaboration with leading experts in mucosal immunity (Dr Joana Neves) and pain research (Dr Franziska Denk) at King’s College London, alongside scientists from the Neuroscience, and Respiratory & Immunology disease areas at AstraZeneca.

The successful candidate will use single cell qPCR/RNA-sequencing and RNA Scope; live cell imaging in primary sensory neurones; ex vivo electrophysiology; and organoid and co-culture approaches to study neuroimmune IL-23/IL-17 signalling in colitis. There will also be the opportunity to conduct an industrial placement at AstraZeneca.

Our team is committed to provide excellent scientific training in a positive and inclusive working environment. We are looking for open and motivated candidates from diverse backgrounds and particularly encourage applications from groups that are currently under-represented in academia.

 

2)    Subcellular parameters regulating efficacy of targeted protein degradation tools   

Supervisor: Dr Catherine Lindon (Pharmacology)

                                                                                                    

Project description

The ubiquitin-proteasome system (UPS) regulates the abundance of cellular proteins through the action of a cascade of enzymes including a ubiquitin ligase that mediates the transfer of ubiquitin onto protein substrates, creating ubiquitin chains that mark them for destruction. The discovery of small molecule ligands for two cellular ubiquitin ligases, cereblon (CRBN) and VHL has sparked an explosion of interest in the concept of ‘targeted protein degradation’ as a new therapeutic approach. This approach harnesses the UPS to destroy targets of clinical interest for which there are small molecule ligands available, by combining the ligands into heterobifunctional molecules (referred to as PROTACs) that recruit a ubiquitin ligase to create a neo-substrate from the target, which is then ubiquitinated and destroyed.  A number of PROTACs with specific activity have now been described and the first have entered clinical trials. Despite these advances, detailed description of the cell biology of PROTACs is missing from the scientific literature.

The project will investigate subcellular parameters governing the activity of a PROTAC tool we have recently developed in collaboration with AstraZenecaAstraZeneca (Wang et al. 2020, bioRXiv doi.org/10.1101/2020.07.22.215814). We will use cell-based assays that probe subcellular events at high resolution and map them to PROTAC action using high content assays available at AZ for measuring the efficacy of different molecules. We propose to identify subcellular parameters governing the efficacy of PROTAC drugs in order to improve the design of this class of drugs. Subcellular specificity in PROTAC action can be exploited in future design of drugs to eliminate distinct subcellular pools of clinically relevant targets.

3)    Structure-guided discovery of novel small molecule inhibitors of Neuropilin-1 (NRP1)

Supervisor: Dr Taufiq Rahman (Pharmacology)

Project description

Neuropilins are a family of transmembrane proteins that are highly expressed in endothelial cells (ECs), upregulated in various tumours and they serve as cell surface co-receptors for vascular endothelial growth factors (VEGFs) and several other growth factors. The ability of Neuropilin- 1 (NRP-1) to bind to and augment the action of some growth factors are consistent with its emerging role as an oncoprotein acting by a number of mechanisms. The latter include enabling tumours to evade the immune surveillance through affecting the function of macrophages  and regulatory T cells (Tregs); promoting angiogenesis, lymphangiogenesis and cancer stemness through promotion of VEGF-A signalling in the ECs and consequently promoting tumour growth and migration. Besides, many reports suggest a direct role of VEGF NRP-1  interaction in tumour cell survival and proliferation. Therefore, quite legitimately NRP-1 has emerged as a potential target towards developing novel anti-cancer drugs. It is also very intriguing to note that the furin-cleaved product of SARS-CoV-2 spike protein also binds to the canonical VEGF-A binding site on NRP-1 and such interaction seems to critically underlie SARS-CoV-2 infectivity. Thus NRP-1 could also be a potential target towards developing novel anti-viral agent against relevant pandemic diseases. To date, there has been some attempts towards pharmacologically interfering with the interaction of NRP-1 with VEGF-A through antibodies, peptides and a few peptidomimetic small molecules. All these agents have been shown to wedge into a pocket (the so called 'tuftsin site) on NRP-1 b1 domain that recognises  a C-terminal arginine residue of VEGF-A. Few studies so far have provided us with encouraging evidence that this pocket is chemically targetable and inhibitors binding to this pocket could manifest significant inhibition of angiogenesis, tumour growth and migration in vivo.

            This project aims at structure-guided identification of novel small molecule scaffolds that will specifically bind to the abovementioned pocket and frustrate NRP-1 and VEGF-A interaction. To date, several apo and inhibitor-bound 3D structures of  NRP-1 are available. We will exploit these structures and perform in silico screening of drug/lead like libraries to identify novel chemical scaffolds as potential hits. The latter will be then evaluated experimentally using suitable biophysical (e.g. thermal shift/isothermal calorimetry) and biochemical and functional (cell-based) assays. With potential hit(s) from initial screening, elucidation of the structure activity relationship (SAR) will also be pursued. Finally attempts will be made to solve the 3D structure of NRP-1 b1 domain with the best inhibitor(s) found in this study using X-ray crystallography. Students keen to work at the interface of chemistry and biology as well as drug design are particularly welcome to apply. Prior experience in protein expression and purification with/without in silico methods will be advantageous but not an absolute requirement.

How to apply

All applications will need to be made through the University Application Portal: https://www.graduate.study.cam.ac.uk/courses/directory/blphpdphc/apply

for further information about the programme and to access the Applicant Portal. Please note that the course code for PhD applications to Pharmacology is BLPH22. Whilst making your online application please make clear that you are applying for AZ funding and the 2-principal investigators you are interested in working with. Your online application will need to include:

  • Two academic references  
  • Transcript  
  • CV/resume
  • Evidence of competence in English   
    If required - you can check using our tool
  • §  Statement of interest (1500 characters)
  • Application cost £70 (you have 3 applications)

 Informal inquires about individual projects should be directed to the supervisors listed above.

Applications need to be submitted by 06th December 2020 by midnight. Applications will be assessed as and when they are submitted. Interviews will take place w/c 11th January 2021.

Please quote reference PL24538 on your application and in any correspondence about these positions.

The University values diversity and is committed to equality of opportunity.

 

 

Dr David James Studentship

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During his life, Dr James was a well-respected Departmental Administrator. His legacy provides scholarships for the most gifted postgraduates to pursue focused and original research. The David James Studentship has provided full financial support for a number of PhD students within the Department since October 2011.

Via PhD studentships, the David James Fund is supporting the next generation of Cambridge pharmacologists, whose work will be crucial to developing better treatments for diseases such as cancer, cardiovascular disease, arthritis, diabetes and Crohn's disease.