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Department of Pharmacology

 

Abstracts of research projects offered for October 2022

Candidates are advised to read about the research interests of members of the Department in conjunction with the following information.

Please find information about funding opportunities here.

 

Department of Pharmacology - MRC Toxicology Unit - Newnham College 4-year PhD Studentship

 

1. 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.

 

2. 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.

 

3. 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

 

4. 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.

 


Dr Catherine Lindon

Targeted protein degradation by the Ubiquitin-Proteasome System (UPS)

Targeted protein degradation occurs through ubiquitin-mediated pathways that bring about destruction of ubiquitin-tagged proteins at the 26S proteasome. Our research seeks to understand how these pathways control cell division and other cell fate decisions, with a focus on the major cell cycle regulator Aurora A kinase (AURKA). AURKA is a target of ubiquitin-mediated degradation by the APC/C-FZR1 ubiquitin ligase, and a key player in several types of cancer. We are also exploring the ability of a new class of drugs, often referred to as PROTACs (Proteolysis Targeting Chimeras), to induce degradation of clinically relevant target proteins, opening up exciting new therapeutic avenues.

We study these questions using quantitative molecular and cell biology techniques, including timelapse fluorescence microscopy and cellular ubiquitination assays, and collaborate with chemists, biochemists and computational biologists. Please see our lab pages and recent publications for more information. Interested candidates should contact Dr Lindon to discuss potential PhD projects.

Key words: ubiquitin, mitosis, APC/C, Aurora kinase, degron, proteolysis, targeted protein degradation, PROTAC

 


Dr Catherine Wilson

Harnessing Myc transcription to drive proliferation in non-regenerative organs

Myc is a transcription factor deregulated in the vast majority of cancers, its expression drives cells into cycle and, if unchecked, this deregulation leads to uncontrolled growth. We use acutely switchable models of Myc to assess the immediate molecular and pathological effects of switching Myc on and off. Using these systems, we have shown that Myc binds to a large set of genes common to all tissues that are involved in cell cycle entry; suggesting Myc is able to drive cell cycle progression in any type of cell. However, we found that despite acutely overexpressing Myc in all tissues, non-regenerative tissues like the heart remained almost entirely resistant to cell cycle entry, due to an inability of ectopic Myc to activate transcription of its target genes once bound.

We have established that Myc driven transcription, and consequently cell proliferation, is critically dependent on the level of P-TEFb activity within a specific tissue. Using the heart as a model system that has very limited capacity for proliferation, we have reactivated Myc transcription and proliferation by increasing the activity of P-TEFb. The aim of this project is to establish if restoring Myc driven transcription and proliferation in non-regenerative cells can be harnessed to stimulate endogenous tissue repair.

Please contact Dr Wilson to discuss the projects offered.

Keywords: Myc, transcription, cell cycle, cardiomyocyte, cardiovascular disease, cancer, regeneration, myocardial infarction.


Dr Ewan St John Smith

Title 1. Changing the gain in pain

Outline

The ability to detect potentially damaging stimuli provides a vital protective function, but in chronic pain syndromes (e.g. osteoarthritis and inflammatory bowel disease) the gain in pain goes wrong and the pain experienced has a major impact on an individual’s well-being. In our lab, we employ a range of molecular biology, electrophysiology and behaviour techniques to understand how sensory neurones function and how they have behaviour changes in chronic pain states, the overall aim being to identify new targets for the treatment of pain.

Recent work has used single-cell RNA-sequencing to describe 7 distinct sensory neurone subsets innervating the distal colon (a prime source of visceral pain), identified the mechanism by which a gene variant encoding the voltage-gated potassium channel Kv6.4 alters neuronal excitability and pain sensation, and that chemogenetic approaches can be used to relieve joint pain. Future research projects will involve continuing to further our understanding of chronic pain.

Primary field: Neuroscience

Keywords: pain, electrophysiology, behaviour

Title 2. Healthy ageing with the naked mole-rat

Outline

Mice are short-lived, but naked mole-rats are long-lived and more importantly age healthily. We investigate a variety of aspects that are involved in healthy ageing, such as the high cancer resistance of the naked mole-rat and potential mechanisms explaining their healthy brains, e.g. we have found that lipid extracts from naked mole-rat brain tissue contain higher levels of cholesterol, a substance contained at high levels in lipid rafts, and the lipid environment within which ion channels sit can significantly affect their activity.

Primary field: Neuroscience

Key words: Electrophysiology, cell biology, ion channels


Dr Hendrik van Veen

Multidrug transporters in microorganisms and cancer cells

Multidrug transport proteins are located in the plasma membrane of cells, where they mediate the extrusion of cytotoxic drugs from the cellular interior to the exterior. These membrane transporters modulate the toxicity and pharmacokinetics of drugs in organisms ranging from bacteria to man. They are a cause of drug resistance in pathogenic microorganisms and cancers.

Using biochemical, biophysical, electrophysiological, microbiological and structural tools, we work on interesting and relevant questions:

  • How are drugs recognised by multidrug transporters and how are they transported?
  • What forms of metabolic energy are used by multidrug transporters, and how is this energy coupled to the drug transport reaction?
  • Is drug transport the primary physiological role of multidrug transporters? Do these transporters also handle small ions, phospholipids, lipopolysaccharides and other physiological substrates, and if so, why and how?
  • Selective inhibitors might improve the drug-based treatment of infectious diseases and cancers. Can we use the novel functional and mechanistic insights to generate inhibitors of multidrug transporters? What are the most efficient ways to inhibit these membrane proteins?

We study essential bacterial and human members of the ABC, MFS and MATE transporter families. Our work involves collaborations with chemists, structural biologists and biophysicists within the UK and abroad. Please, visit our lab website for further information, and feel free to contact Rik van Veen (hwv20@cam.ac.uk) to discuss possible PhD and MPhil projects.

Keywords:Antibiotic and anticancer drug resistance; multidrug transporters; transport mechanisms; physiological substrates; novel inhibitors.


Professor Laura Itzhaki

Tandem-repeat proteins: Physiological and pathological functions, therapeutic intervention, synthetic biology and drug development

The major focus of our research is a class of proteins with very distinctive architecture, known as tandem-repeat proteins (e.g. ankyrin, tetratricopeptide and armadillo repeats), which are frequently deregulated in human diseases such as cancers and respiratory and cardiovascular diseases. These proteins function as scaffolds for molecular recognition and binding hubs for assembling large macromolecular machines.

The term ‘scaffold’ implies a rigid architecture; however, as suggested by their Slinky spring-like shapes, it is thought that repeat proteins utilise much more dynamic and elastic modes of action. For example: stretching and contracting to regulate the activity of a bound enzyme; reversible nanosprings to operate ion channels; proteins that wrap around their cargoes to transport them in and out of the nucleus. The modular architecture of repeat proteins makes them uniquely amenable to the dissection of their biophysical properties as well as the rational redesign of these properties. The following PhD projects are available:

  1. Exploiting the design-ability of repeat proteins to build artificial proteins with applications in synthetic biology (multivalent and multi-functional repeat proteins designed to rewire signalling pathways), repeat-protein therapeutics as alternatives to antibodies (designed repeat proteins to trigger the destruction of disease-associated targets pathways), and nanotechnology (self-assembling repeats proteins to build functional nanomaterials).
  2. Peptide inhibitors to target disease-associated repeat proteins for therapeutic benefit. 
  3. Protein engineering and design to determine how the distinctive structures of repeat proteins control their functions in the cell - e.g. building artificial repeat proteins to act as cellular force sensors. 

Research in our group is at the interface between biology and chemistry; we also have close collaborations with computational groups and synthetic chemistry groups in Cambridge, and therefore students will be able to learn a broad range of techniques and approaches, including protein engineering, biochemistry and biophysical analysis including single-molecule techniques, cell biology and medicinal chemistry. We also work closely on biotherapeutics development with PolyProx Therapeutics, a biotech company recently spun out of the academic group.

Keywords: protein engineering, protein design, targeted protein degradation, cancer, biotherapeutics, mechanobiology


 

Dr Matthew Harper

Platelet procoagulant activity: regulation and inhibition

Platelets are necessary for normal haemostasis but platelet activation at the wrong time or place drives arterial thrombosis, leading to heart attacks and ischaemic stroke. One of the prothrombotic roles of platelets is to enhance coagulation by exposing phosphatidylserine (PS) on their outer surface and by releasing procoagulant extracellular vesicles (EVs).

In the Harper lab we aim to understand how platelet PS exposure and EV release are regulated, and whether we can pharmacologically inhibit these dangerous processes to reduce thrombosis.

Please contact Dr Harper to discuss potential MPhil or PhD projects before applying.

Keywords: platelets, thrombosis


Dr Paul Miller

Study of Ion Channels and Biologic Partners

Ion channels play myriad functional roles in fundamental biology, for example by coordinating and powering muscle contraction, by generating axon potentials, and by mediating synaptic communication between neurones throughout the peripheral and central nervous system (CNS). As such, ion channels represent major therapeutic targets with small molecules against them being the third best selling group of prescribed drugs. Despite this only a tiny fraction of channels are currently targeted from the estimated 400 predicted human ion channel genes.

In recent decades antibody therapeutics (biologics) have rapidly risen to prominence in the drug market. One reason for the success of these agents is improved target specificity. However, no biologics against ion channels have yet made it into the clinic. Technically, ion channels represent challenging targets for the generation of useful biologic binders and modulators, in part due to difficulties in protein production of native forms, and in part due to a lack of penetrance of biologics into the CNS. The impact of breakthroughs in this area cannot be underestimated. Currently my research is aimed at using electrophysiological, biochemical, protein engineering and structural biology approaches to understand and develop novel antibody (nanobody) modulators with unique pharmacological properties against GABAARs. These receptors are the principal mediators of inhibitory neurotransmission throughout the human brain, and targets for essential clinical drugs such as benzodiazepines, Z-drugs and intravenous anaesthetics.

Additionally, I am interested in exploring alternative disease relevant neuronal ion channels from the perspective of structural biology, and to investigate antibodies against them as pharmacological modulators. Naturally, following on from these studies aims are to test these proteins in relevant systems to uncover their impacts in neuronal function and to realise their therapeutic potential.

These projects are currently unfunded, and so I particularly welcome applicants who would make strong candidates for prestigious scholarships, such as Gates Cambridge, Cambridge Trust, Vice Chancellor’s Awards, or similar.

Keywords: Cryo-EM, ion channels, electrophysiology, antibody modulators

 


Dr Taufiq Rahman

Identifying novel modulators of ion channels and receptors of therapeutic interests

We employ various computational (cheminformatics, structural bioinformatics, molecular dynamics simulation) approaches supported by complementary wet experiments (calcium imaging, electrophysiology, biochemical and biophysical assays) to study the molecular details of ligand recognition, ligand modulation, structural variation and dynamics of some ion channels and G-protein coupled receptors (GPCRs). An overarching aim of the group is to rationally identify novel chemical probes/modulators of these signalling proteins. We often explore, computationally and experimentally, existing and investigational drugs to evaluate potential drug repurposing potential/off target liabilities involving some of these ion channels and receptors. For some targets implicated in microbial infections, cancer, pain, inflammation and diabetes, we have ongoing collaboration with academic groups and industrial partners towards developing novel lead molecules for future drug development.

Please contact Dr Rahman to discuss potential MPhil or PhD projects before applying.

Primary Field: Pharmacology, Drug Design, Chemical Biology

Keywords: computer aided drug design, GPCR, ion channel, cell signalling, electrophysiology


Dr Walid T. Khaled

Identification and disruption of heterotypic cellular interactions during tumorigenesis

The early stages of tumour development are poorly understood and is an area which has the potential to improve the rates of early detection, prevention and treatment of cancer. Recent sequencing studies of normal tissue suggest that acquiring putative oncogenic drivers is not sufficient to initiate tumour development. This suggests a key role for the cell of origin, differentiation state and the microenvironment in mediating tumour initiation.

Research in our laboratory focuses on defining the early cellular and molecular events that drive tumour initiation and development. We particularly focus on how the cell of origin affect the differentiation trajectory of nascent tumour cells and dictate changes in the microenvironment thus, enabling tumour growth and immune evasion.

In this project the candidate will mine scRNAseq data we have generated in the lab from mouse models of breast cancer to identify putative and novel heterotypic ligand-receptor interactions between different cell types in the mammary gland. The candidate will then use primary mouse and human organoids to validate and understand the mechanism of these heterotypic interactions before attempting to disrupt them.

Keywords: single cell genomics, mouse models, organoids