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Studentships

BBSRC Doctoral Training Partnership (DTP)

The University of Cambridge is offering up to 30 four-year BBSRC-funded studentships starting in October 2019. A wide range of projects are available across many world-class departments (including the Department of Pharmacology) and research institutes under the four broad themes of:

The first 6 months is spent completing training in Statistics, Computational and Systems Biology, and Research Skills (New Ways of Working) and undertaking two 10-week rotation projects, either at the University or at one of the partner organisations, before progression to a PhD project. An exciting element of the programme is a three-month internship to gain experience in a non-academic environment, including industry, the media, charities, education and government.

UK and EU students who meet the UK residency requirements will be eligible for a full studentship. Students from EU countries who do not meet the UK residency requirements may still be eligible for a fees-only award. Further information can be found at https://bbsrc.ukri.org/skills/investing-doctoral-training/dtp/

We encourage students who are interested in a research area that is eligible for BBSRC funding to apply for the DTP programme. Detailed information on application can be found here:

bbsrcdtp.lifesci.cam.ac.uk/prospective

Students can apply to the DTP and also the Department for a PhD, however two separate applications will need to be made under one application fee.

The BBSRC Doctoral Training Partnership PhD course code is BLBB22.

The course code for the PhD (Probationary) in Pharmacology is BLPH22.

All EU candidates seeking funding should use the APPLICANT PORTAL to apply to the Gates Cambridge Trust (http://www.gatesscholar.org/; deadline 3rd January 2019) and other centrally- available funds (including the Cambridge Trust www.graduate.study.cam.ac.uk/finance/funding) if they are seeking support from any Cambridge source.

 

Astra Zeneca 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/EU candidates only.

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 2019. A maximum of four studentships will be awarded in this application round.

4-year Projects available

1)    Cannabinoid receptor function in arthritic pain

Supervisors: Dr. Ewan St. John Smith (Pharmacology) / Dr. Fraser Welsh (AstraZeneca)

Project description

Chronic pain is common and poorly treated, estimates suggesting the prevalence of chronic pain to be ~45% in the UK and that approximately two-thirds of chronic pain patients receive inadequate treatment of their pain. Pain resulting from arthritic conditions is particularly common and with an ageing population the prevalence of ageing-related conditions like osteoarthritis will increase. The need therefore exists to better understand the mechanisms that drive pain in order to facilitate the development of new treatments.

Cannabis has been used for treating various ailments for hundreds of years and as of 2017 medical marijuana is legalised in 55% of US states with chronic pain being a qualifying condition for its use in the vast majority of states. Reduced pain is likely due to the activation of cannabinoid receptors (CB), which are expressed throughout the nervous system. However, there are various issues surrounding the use of medical marijuana, including its ability to cause adverse psychiatric side effects, including psychosis, through activation of CB receptors in the brain. Studies with transgenic mice in which the CB1 receptor has been knocked out in just the primary sensory neurones demonstrate that targeting of peripherally expressed CB1 receptors could be beneficial in treating inflammatory pain. Moreover, CB agonists cause significantly less analgesia in mice lacking peripheral CB1 receptors. Lastly, levels of endocannabinoids are locally increased in inflammation, thus suggesting that the endocannabinoid system has evolved to regulate pain sensation. All this evidence points to a key role for peripheral CB1 receptors underlying cannabinoid-mediated analgesia and indeed, a peripherally restricted CB receptor agonist produces analgesia.

In order to further understand the role of endocannabinoids and CB receptors in pain, we will use mouse models of rheumatoid arthritis and osteoarthritis to firstly determine how these pain conditions modulate endocannabinoid levels and CB receptor expression. This will be done by retrograde tracing of knee-innervating sensory neurones, followed by induction of arthritis, and then using a combination of immunohistochemistry and single-cell qRT-PCR to determine expression levels in sensory neurones at different time points, alongside analysis of endocannabinoid levels in knee joints through liquid chromatography/mass spectrometry. We will further combine retrograde tracing with models of arthritis and then conduct electrophysiology on isolated, knee-innervating sensory neurones to determine changes in CB receptor function. In addition, we will examine how arthritis modulates both natural behaviour in mice (e.g. digging behaviour and dynamic weight bearing) and how modulation of CB receptor signalling modulates these behaviours, the drugs and approaches (e.g. virally-mediated chemogenetics) used being determined by the results of our expression and functional analyses.

Relevant references:

Chakrabarti, S., Pattison, L.A., Singhal, K., Hockley, J.R.F., Callejo, G. and Smith, E.S. (2018). Acute inflammation sensitizes knee-innervating sensory neurons and decreases mouse digging behavior in a TRPV1-dependent manner. Neuropharmacology, in press, doi 10.1016/j.neuropharm.2018.09.014

Hockley, J.R.F., Taylor, T.S., Callejo, G., Wilbrey, A.L., Gutterridge, A., Bach, K., Winchester, W.J., Bulmer, D.C., McMurray, G. and Smith, E.S. Single-cell RNAseq reveals seven classes of colonic sensory neuron. Gut, in press, doi 10.1136/gutjnl-2017-315631

Wright, A. J., Husson, Z. M. A., Hu, D. E., Callejo, G., Brindle, K. M. and Smith, E. S. (2018) Increased hyperpolarized [1-13C]lactate production in a model of joint inflammation is not accompanied by tissue acidosis as assessed using hyperpolarized 13C-labeled bicarbonate. NMR Biomed e3892

2)    Vagally mediated nutrient signalling in mouse and human intestine

Supervisor: Dr. David Bulmer (Pharmacology)                                                                                                       

Project description

The stimulation of vagal afferent fibres by gut hormones released from enteroendocrine cells in response to nutrients, is an important physiological mechanism in the control of food intake and gut function. Therapeutically, the activation of this pathway by nutrients delivered directly into the distil intestine is key to the improvement in body weight seen following bariatric surgery in obese patients. A significant investment has therefore been made in the development of drugs that can stimulate intestinal hormone release in the hope that the success of bariatric surgery can be replicated in a pill. For the most part approaches targeting the activation of intestinal afferents by gut hormones or nutrients directly have largely been ignored. Despite this, vagal afferents do offer an excellent opportunity for therapeutic intervention, with a good record of translation for gastrointestinal disease. In particular manipulation of receptors and ion channels co-expressed by vagal afferents sensitive to gut hormones are likely to provide additive or synergistic benefits to existing monotherapies that enhance incretin release.

The electrophysiological study of vagal afferent signalling within the intestine is technically challenging and many groups utilise co-culture approaches to examine signalling between enteroendocrine cells and nodose ganglia. The major limitation of these culture systems is the absence of afferent fibres endings, the natural site of signal transduction between these cells. To address this issue, we have recently established an ex-vivo tissue preparation of the terminal ileum and ascending colon (the two major sites of nutrient signalling implicated in the success of bariatric surgery) demonstrating robust afferent responses to prototypic appetite regulating hormones e.g. CCK and PYY, and markers of vagal afferent subpopulations such as neurotensin, in addition to nutrients such as peptones, or the stimulation of enteroendocrine cells using a cocktail of angiotensin II & IBMX.

We believe this ex vivo model offers a unique opportunity to study neuronal signalling in response to nutrient ingestion in the gut and can be readily translated by studies using isolated human tissue.

The aim of this studentship will therefore be to develop this model and our understanding of nutrient driven vagal afferent signalling further by:

a) characterising vagal afferent fibres populations innervating the terminal ileum and proximal colon using transcriptomic (single cell QPCR/RNA sequencing), immunohistochemical and functional (ex-vivo electrophysiology) approaches in collaboration with researchers from the Department of Pharmacology, Dr Ewan St. John Smith and Dr Walid Khaled; and the Institute of Metabolic Sciences, Prof Frank Reimann and Prof Fiona Gribble,

b) investigating how different receptors and channels modulate vagal afferent signalling in response to nutrients.

c) developing the electrophysiological recording of intestinal afferent activity in response to the application of nutrients in the human gut ex-vivo.

3)    Exploring the therapeutic potential of protein PAMs of GABAA receptors

Supervisor: Dr. Paul Miller (Pharmacology)

Research in the Miller lab examines immunogenically ‘raised’ Nb PAMs of GABAA receptors. GABAA receptors are the principal mediators of inhibitory neurotransmission in the central nervous system (CNS). Small molecule PAMs such as benzodiazepines (e.g. Valium) and non-benzodiazepines (e.g. Zolpidem) are used to treat generalized anxiety disorder, epilepsy, muscle spasm and insomnia. Critically, different subtypes have been associated with distinct roles in addiction, sedation, anxiety, and nociception. Unfortunately, the selectivity of small molecule PAMs remains unsatisfactory, and for clinical drugs this contributes to dependence, amnesia, ataxia, tolerance and withdrawal. This barrier restricts generation of therapeutics to better treat these established indications, and target novel illnesses linked to GABAA receptor dysfunction, such as postpartum depression, autism, pain and stroke.

The extended contact area of protein-protein interactions mean Nbs overlap with subtype-specific epitopes on GABA-A-Rs. Nanobodies have been identified that are highly efficacious PAMs and have high (10-1000-fold) subtype selectivity between subtypes (for example see [1]). Nevertheless, so far they have only been superficially explored in physiological and disease relevant systems and require more characterisation. Furthermore, because GABA-A-Rs are predominantly expressed in the CNS, strategies will be employed to transport nanobodies across the blood brain barrier (BBB), which normally blocks entry of protein therapeutics, following systemic injection [2, 3]. In addition, there is growing realization of a role for GABA-A-Rs peripherally, for example in visceral nociception [4]. Studies to test subtype selective nanobodies in such systems, where crossing the BBB would not be required, is of high interest, and my collaborators, Dr Ewan Smith and Dr David Bulmer (Pharmacology) are experts in this area. Protein injections and transcardial perfusions (for immunohistochemistry to establish CNS delivery) will be done in the Smith lab. Protein engineering, protein chemistry and production, pharmacological evaluation, electrophysiology in recombinant systems, ELISAs for pK analysis, immunohistochemistry will be done in the Miller lab. Successful delivery of nanobodies into the CNS in vivo will lead on to behavioural studies, done through collaborations with academia or AZ.

References

1)     Miller, P.S., et al. Heteromeric GABAA receptor structures in positively-modulated active states. Online through BioRxiv, (2018). Submitted to eLife, undergoing minor revisions.

2)     Weber, F., et al. Brain Shuttle Antibody for Alzheimer's Disease with Attenuated Peripheral Effector Function due to an Inverted Binding Mode. Cell Rep 22, 149-162 (2018).

3)     Thom, G., et al. Enhanced Delivery of Galanin Conjugates to the Brain through Bioengineering of the Anti-Transferrin Receptor Antibody OX26. Mol Pharm 15, 1420-1431 (2018).

4)     Hockley, J.R.F., et al. Single-cell RNAseq reveals seven classes of colonic sensory neuron. Gut (2018).

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 £60 (you have 3 applications)

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

Applications need to be submitted up 30th Nov 2018. Applications will be assessed as and when they are submitted. Interviews will take place between 15th and 31st, January 2018.

Please quote reference PL17048 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

The Department is able to offer a Studentship, for a home or EU student, due to the generosity of our former Colleague

davidjamesBWDr David James. 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.

And through 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, arthritis, diabetes and Crohn's disease.

The studentship will cover a stipend equivalent to the standard Research Council rate (£14,777 per annum for 2018/19), research costs and tuition fees at the UK/EU rate, for three years and is available for the successful UK or EU student - but please see information here regarding EU fee status for entry 2019 and onwards: https://www.graduate.study.cam.ac.uk/finance/fees

 

Application process. Please apply via the APPLICANT PORTAL using the course code for the PhD (Probationary) in Pharmacology is BLPH22 and indicate on the application form your interest in the David James Scholarship.