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Projects available for October 2021

Abstracts of research projects offered for October 2021

The research interests of all the members of the Department are available at www.phar.cam.ac.uk/research.

Candidates are advised to read these research interest pages in conjunction with this information.

 

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. Please see www.graduate.study.cam.ac.uk/finance/funding for funding opportunities.

 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) and shown that upregulation of TRPV1 in knee-innervating sensory neurones is a good target for ameliorating inflammatory 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 – dealing with reactive oxygen species

 

Outline

Lipid peroxidation occurs as a result of reactive oxygen species (ROS) activity. Accumulative peroxidative damage is one hypothesis underpinning ageing-induced decline in bodily function. Mice are short-lived, but naked mole-rats are long-lived and thus we hypothesise that naked mole-rat lipid membranes and ion channels contained therein are more resistant to ROS-mediated modulation. In addition, 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 an ion channel sits can significantly affect its activity. We will examine how ROS and lipid raft modulation affect the excitability of naked mole-rat neurones, as well as the activity of specific ion channels that are known to be modulated by lipid peroxidation products, such as members of the transient receptor potential (TRP) ion channel family.

 

Primary field

Neuroscience

 

Key words: Electrophysiology, cell biology, ion channels

 

 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 (polyprox.com), a biotech company recently spun out of the academic group.

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

 

Prof. Colin Taylor:


Structure and function of Ca2+ channels within dynamic organelles

How does Ca2+, an element and the simplest of all intracellular messengers, selectively regulate so many cellular activities? We address this question by examining how the behaviour of intracellular Ca2+ channels, notably IP3 receptors, and the organelles in which they reside lead to complex changes in intracellular Ca2+ concentration. We are exploring the structural basis of IP3 receptor gating and the contribution of dynamic intracellular organelles to shaping cytosolic Ca2+ signals. The ER, where most IP3 receptors reside, forms intimate contacts with most other organelles. Dynamic regulation of these interactions may be as important as receptor-regulated formation of IP3 in determining how cells generate and respond to cytosolic Ca2+ signals. Furthermore, IP3 receptors move within the ER. We do not understand the relationships between these dynamic IP3 receptors and the much smaller number of immobile IP3 receptors that appear to generate most Ca2+ signals. What licences immobile IP3 receptors to respond? We apply super-resolution optical and electrophysiological methods alongside gene-editing with CRISPR/cas9 of native signalling proteins to explore, often at the single-molecule level, the structural basis of IP3 receptor activation and the dynamics of Ca2+-handling organelles. We apply these methods to both 'work-horse' cells like HEK293 cells, and to primary cells: bronchial and vascular smooth muscle (cAMP/Ca2+ interactions controlling contraction), fibroblasts, astrocytes (spatial organization of intracellular ATP provision) and glioma cells (migration and invasion). Our work, including that of PhD students, is supported by extensive national and international collaborations with chemists, structural biologists and mathematicians, and with partners in industry.

Keywords: Cell signalling, patch-clamp recording, super-resolution microscopy, gene-editing, ion channel, Ca2+, cyclic AMP, intracellular organelles, smooth muscle, fibroblast, astrocyte, glioma.

 

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.

 

Dr David Bulmer:

What are the mechanisms of abdominal pain during colitis?

Abdominal pain has a profoundly negative effect on the quality of life experienced by patients with inflammatory bowel disease (IBD). Current immunosuppressant therapies although effective for the treatment of inflammation, are suboptimal for pain with many patients continuing to feel pain during remission.  

To address this problem work in my lab has utilised tissue from patients with IBD to identify mediators and mechanisms responsible for the activation of pain sensing nerves within the gut (see Hockley et al, 2014 PAIN 155 (10): 1962-1975; McGuire et al, 2018 Gut 67(1)). By identifying which mediators are key to the production of pain and how they activate pain sensing nerves we can develop new drugs to switch these processes off and treat pain. This studentship will explore the effects of putative mediators of abdominal pain, identified from a whole transcriptome analysis of IBD patient tissue, on pain sensing neurones that innervate the gut. To do this we will utilise ex vivo electrophysiological recording techniques and calcium imaging to study the effect of selected mediators on neuronal activation.

Keywords: Pain, inflammation, neuroscience, pharmacology

 

Dr Taufiq Rahman

We are interested in finding novel endogenous and exogenous modulators of some ion channels (especially those that are Ca2+ permeable) and GPCRs that are of therapeutic interests. We are also actively involved in drug repurposing against some chosen targets. The underlying theme of our work largely derives from the fact that novel modulators often reveal novel pharmacodynamics and this may potentially inform us with new knowledge about how a signalling protein like an ion channel or a GPCR functions from structural point of view. We routinely use various in silico modelling and screening approaches that are complemented by prospective cell-based, biochemical, biophysical and electrophysiological assays. Please visit our lab pages for more information and recent works. If interested, contact Dr Rahman to discuss potential projects for M.Phil/PhD. For funding, please visit www.graduate.study.cam.ac.uk/finance/funding.

 

Keywords: ion channels, G-protein coupled receptors, calcium signalling, electrophysiology, computer-aided drug design

 

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