Applications are invited for a 4-year Department of Pharmacology – MRC Toxicology Unit – Newnham College PhD Studentship as part of the School of the Biological Sciences Doctoral Training Program (SBS DTP) to conduct research in the Department of Pharmacology and MRC Toxicology Unit available from October 2022. The Studentship will be awarded on a competitive basis and applicants will be expected to demonstrate a strong academic background and an aptitude for research.
The studentship is funded by the Department of Pharmacology via the David James Studentship scheme, the MRC Toxicology Unit, and Newnham College. The successful applicant will become a member of Newnham College, which offers a lively and welcoming women’s College, and will have the opportunity to take part in SBS DTP activities.
This award will cover UK University fees and a maintenance allowance at the RCUK rate. Information about University fees and standard maintenance costs for 2022/2023 is available here.
Applicants should have or be about to achieve a first or upper second-class degree from a UK university or an equivalent standard from an overseas university and meet the University of Cambridge entrance requirements. Full details of the University’s entrance requirements are specified here.
PROJECTS
Dr David Bulmer (Pharmacology) and Dr Kiran R. Patil (MRC Toxicology)
Gut bacterial modulation of sensory nerve signaling in response to drugs
Gut microbiota is now well recognized as a modulator of a variety of physiological processes including immune response and nerve signaling. Recently, the microbiota has been identified as a contributor to therapy-induced pain and other side effects linked to sensory output from the GI tract. A mechanistic understanding of the links between drug-microbiota interactions and microbiota-nerve signaling thus offers new avenues to reduce dose-limiting side effects and improve overall therapeutic success. Yet, most studies in this area remain correlative and limited to a few drugs. This project will systematically assess nerve signaling modulatory effects of gut bacterial metabolites by combining in vitro microbiomics and metabolomics (Patil lab) with ex vivo assessment of nerve signaling & sensory output from the GI nerve fibres (Bulmer lab). Our hypothesis is that the drug-induced changes in bacterial secretome – as recently identified by the Patil lab – will alter the impact of bacteria on nerve signaling and thereby the downstream effects including pain.
Notably, many of the known mechanistic links between microbiome and nervous system are secreted small molecules. We will build upon this by performing in vitro assays followed by in vivo validation experiments to identify novel small molecule modulators. The project will start with testing supernatants of defined gut bacterial communities treated with drugs (or controls) using nerve signaling assays. Those showing substantial effects will be further analyzed in vivo while biochemical and metabolomics assays will be performed in parallel to identify the causative agents. Multi-omics analyses will be used to dissect mechanisms for the identified compounds. Overall, the project is expected to reveal novel bacterial metabolites with nerve signaling modulatory function, as well as establish a novel discovery platform.
COVID-19 vaccine antibodies -- mechanisms of platelet activation
Dr Matthew Harper (Pharmacology) & Dr James Thaventhiran (MRC Toxicology)
Vaccines are one of the stand-out successes of modern medicine. However, side effects of vaccines can cause serious complications for those affected and can reduce vaccine uptake. Blood platelets have been repeatedly implicated in vaccine side effects, such as immune thrombocytopenia (low platelet count, which increases bleeding risk). Most recently, thrombosis and thrombocytopenia were seen in some patients following the ChAdOx1 (Oxford) vaccine against SARS-CoV2. Activation of regulated cell death pathways in platelets promotes both thrombosis and thrombocytopenia. Understanding how vaccination-induced antibodies may regulate platelet cell death pathways is key part of understanding vaccination-induced side effects. In this project the student will use single-cell RNA and DNA sequencing of stored B cells collected from vaccine recipients to identify the sequence of identity of platelet targeting antibodies. They will use mammalian expression systems to make these antibodies and then explore the molecular mechanisms by which these antibodies activate platelets to promote thrombosis and thrombocytopenia.
Naked truth: what epigenetic mechanisms sustain healthy ageing in the naked mole-rat?
Dr Ewan St. John Smith (Pharmacology) & Dr Mathew Van De Pette (MRC Toxicology)
Understanding the molecular and cellular mechanisms of how epithelial tissues are maintained in a homeostatic state through our lifetime remains a major challenge. We have limited understanding of how age impacts the cellular composition and dynamics of epithelial tissues, even though age is one of the most significant risk factors for development of malignant disease. The naked mole-rat (NMR, Heterocephalus glaber) provides a unique opportunity to study the impact of ageing in a system largely resistant to age-regulated disease. The NMR is an exceptionally long-lived rodent, which exhibits healthy ageing and a mortality rate that defies Gompertzian laws by not increasing with age over its 30+ year lifespan. We hypothesise that, in accordance with the disposable-soma theory of ageing, the NMR (epi)genome has selected for mechanisms enabling healthy ageing. We will test this through RNA-sequencing and bisulphite-based genome-wide analysis of DNA methylation of three different epithelial tissues, mammary gland, lung and intestine, in young and aged NMR samples. In addition, using in vitro approaches we will test how NMR epithelial cell lines respond to genotoxic stress and so-called epidrugs. We have shown that NMR cells can be induced to undergo oncogenic transformation, but it remains to be determined if a resistance to genotoxic stress and/or epigenetic modifying agents play a role in their cancer resistance.
Keywords: ageing, epigenetics, cancer
Techniques: cell culture, bioinformatics
The Role Transcription Elongation in Cardiomyocyte Proliferation
Dr Catherine Wilson & Dr Ritwick Sawarkar
There are 23 million heart failure patients worldwide, which has an enormous socio-economic impact. The only effective treatment for end-stage heart failure is heart transplantation, and regeneration of the heart is the best potential alternative treatment. Our recent findings demonstrate that combined MYC and Cyclin T1 expression can elicit extensive cellular proliferation of adult mammalian cardiomyocytes. MYC is a promiscuous transcription factor that binds to open chromatin and drives pervasive transcriptional elongation via direct recruitment of P-TEFb (Cyclin T1 and CDK9). The output of MYC is blunted in the heart by the endogenous low level of P-TEFb in cardiomyocytes.
Another key gene that drives widespread adult mammalian cardiomyocyte proliferation is YAP. When active, YAP associates with TEAD transcription factors and drives widespread transcriptional elongation via the recruitment of P-TEFb. Therefore, both the YAP and MYC signalling pathways act downstream from mitogenic signals and drive widespread release of paused RNA Pol II.
The aim of this project is to establish whether the mechanism of action of these two key drivers of cardiomyocyte proliferation overlap and hinge upon genome-wide transcriptional amplification. We will use human cardiomyocytes that have been differentiated from hESCs, genome wide sequencing technologies and cell biology assays. Specifically we will define the molecular mechanism of MYC and YAP driven proliferation in cardiomyocytes and determine the synergy or interdependence of MYC and YAP driven cardiomyocyte proliferation.
APPLICATION PROCEDURE
Step 1: Contact supervisors
The projects offered will be co-supervised by research groups in Pharmacology and MRC Toxicology. The Departments are situated adjacent to each other and are linked by shared communal spaces. A list of supervisors and projects can be found here. Make contact with potential supervisors by email to find out more information about projects. Include in your email your CV, detailing your academic record and contact details for 2 academic referees.
Step 2: University Application
If the supervisors wish to support you for the competition, they will ask you to apply formally to the University using the online application form (Applicant Portal). For more information, see https://www.phar.cam.ac.uk/postgraduate-admissions
Project-related questions may be addressed directly to the supervisor. Requests for general information or enquiries about procedures, including advice if you have already submitted an application to the Department of Pharmacology or MRC Toxicology Unit, can be made via email to phar-gradoffice@lists.cam.ac.uk.
Online applications with ALL supporting documentation to be submitted by
12 midday on Tuesday 28 February 2022 at the latest.
Interview dates to be confirmed.
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