DTP3 Cohort 2 Details
Alkiviadis Anagnostopoulos
University of Liverpool
Supervisors: Prof Georgios Oikonomou, Dr Nicholas Evans, Dr John Tulloch and Dr Christopher Stewart
Deciphering the role of host-pathogen-microbiome interactions in the development of bovine digital dermatitis.
Project Description: Digital dermatitis (DD) is a painful, infectious, foot skin disease affecting ruminants worldwide. In addition to pain and compromised animal welfare, DD is also associated with reduced milk yield, feed intake, and reproductive performance, and estimated to cost the UK dairy industry more than £74 million per year. Bacteria of the genus Treponema are considered the main pathogen associated with DD; however, the aetiopathogenesis and transmission patterns of the disease have not yet been elucidated. Current control strategies are generic and lack a substantial evidence base, relying on the empirical use of topical antibiotics and footbathing solutions containing heavy metals, such as copper sulphate, or formalin (carcinogen). We propose here to conduct a multidisciplinary, integrated study that will allow us to elucidate the role of host-pathogen-microbiome interactions in the development of DD, and advance our understanding of the disease’s epidemiology, thereby offering tools to prevent the disease.
NLD Research Thematic Areas: Agriculture and Food Security
Personal Background: I received a degree in Veterinary Medicine from the Aristotle University of Thessaloniki in Greece and for the past few years I have worked as a research assistant in the University of Liverpool. I have been involved with research into the aetiopathogenesis of lameness in dairy cattle and I have developed an interest in machine-aided lameness detection and control. I am optimistic that our PhD research will help us better understand the aetiopathogenesis of Digital Dermatitis and its transmission patterns and have positive implications for the dairy industry.
Charlotte Brown
Newcastle University
Supervisors: Dr Sergey Melnikov, Dr Peter Chivers and Dr Peter Etchells
Using ribosomes as molecular thermometers to predict optimal growth conditions and peer into the ancient history of life on Earth
Project Description: Our ability to study how organisms have historically adapted to new environments, especially during the early evolution of life, remains a challenge because it is largely limited to mineral analyses and computer simulations, many of which are fraught with technical pitfalls. For example, we do not know what the ocean temperatures were between 3 and 1.5 billion years ago. Ribosomes are believed to be the most ancient molecular machines in living cells, dating back to the origin of life 4 billion years ago, and have therefore been extensively used as ‘molecular clocks’ to understand the timing of the evolution of life on our planet. Our ongoing study indicates that ribosomes (specifically, zinc-coordinating ribosomal proteins) can be also used as ‘molecular thermometers’ to estimate optimal growth temperatures.To investigate this problem, I will be helping to establish a new method to use ribosomal genes to show an estimation of optimal growth temperatures for living and extinct organisms. I will be using cryo-electron microscopy (cyro-EM) to determine structures of ribosomes from heat and cold adapted organisms, and then use bioinformatics to gain an understanding of the genomic differences in these organisms and how ribosomes have adapted to different temperatures. I will also be relating this information to living organisms by using protein biophysics and plant mutagenesis with supervisors in Durham.This study will reveal how ribosomes adapt to extreme temperatures and how ribosomes can be used as ‘molecular thermometers’: instead of running laboratory experiments, we will be able to accurately predict the optimal growth environment for a given organism by sequencing its ribosomal genes. This may forever change our approach to studying unculturable and extinct species and the history of climate change on our planet.
NLD Research Thematic Areas: Industrial Biotechnology (IB), Synthetic Biology and Structural Biology
Personal Background: I am a scientist on a mission to prove that having disabilities doesn’t have to be an obstacle to becoming a scientist. My fascination with genetics started whilst I was in high school as I decided to find out if my hearing loss had a genetic cause, for which I didn’t get an answer as there has been very few genes for hearing loss identified. In 2013 I completed a BSc in Human Biology degree at Sheffield Hallam University and then in 2018 I obtained an MSc in Computational Systems Biology at Newcastle University. Before joining the graduate school at Newcastle University, I have been employed by Sheffield Children’s Hospital, where I worked on a database for newborn screening, Public Health England, and Great Ormond Street Hospital/University College London where I helped with data analysis of a follow up of children with microencephaly. Whilst working as a Bioinformatician at PHE, I helped improve the automated detection of pathogenic strains of E. coli to enable rapid and personalised therapies for patients within the NHS.
Eleanor Hargreaves
University of Liverpool
Supervisors: Dr Igor Barsukov, Dr Tobias Zech and Prof Che Connon
Understanding the function of microtubule-associated signalling networks in health and disease: role of adaptor proteins in network assembly
Project Description: My project will investigate the molecular system that is key to the regulation of all cellular processes - microtubule (MT) signalling networks - in healthy and diseased states. Focusing on MT adaptor proteins that control network assembly and recruitment of other proteins through a set of interconnected interactions. The complexity of signalling requires the use of advanced biological methods, starting with NMR and X-ray crystallography to determine adaptor protein structures to mutagenesis and high-resolution fluorescent microscopy. Joining all this information together, the aim is to identify critical components of signalling networks and test their potential as drug targets.
NLD Research Thematic Areas: Systems Biology and Technology Development; Industrial Biotechnology (IB), Synthetic Biology and Structural Biology; Ageing, Diet and Health
Personal Background: My personal and scientific career are deep rooted in the city of Liverpool. Being a born and bred Liverpudlian to undertaking an undergraduate degree in Biomedical Sciences at Liverpool John Moores University, then a masters in Translational Medicine at the University of Liverpool. For the past year I have worked within the UoL as a research assistant inspiring me to pursue a PhD within the field of molecular biology.
Emilia Gregory
University of Liverpool
Supervisors: Dr Natalia Sanchez-Soriano and Dr Olena Riabinina
Investigating the role of Tau in synaptic architecture and function
Project Description: Neurodegenerative diseases, including Alzheimer's and Frontal-temporal Dementia, leads to the dysfunction of synaptic machinery causing cognitive, sensory and motor decline. The aim of the project is to understand the role of Tau in synapse regulation during health, ageing and disease. Tau is a promising therapeutic target for treating neurodegenerative diseases as it is linked to physiological ageing and the pathogenesis of neurodegenerative disorders. Preliminary studies have already shown that Tau interacts with a variety of synaptic proteins, but functional links are yet to be identified. This will be further explored in the model organism Drosophila, whose genetic amenability, synaptic machinery conservation and robust behavioural assays will allow us to identify a functional links between Tau and its binding partners.
NLD Research Thematic Areas: Regenerative Biology, Stem Cells and Neuroscience, Ageing, Diet and Health
Personal Background: I recently graduated from The University of Manchester with an MSci Biochemisty degree, where I developed an interest for understanding the biochemical basis of diseases and neurodegeneration. For my final year project I chose to work in a Drosophila lab investigating the mechanisms by which de novo Rac1 mutations caused a developmental disorder, which also severely disrupted neurodevelopment. As my first time working with Drosophila I became fascinated with the versatility it offers to uncover the functions of proteins in neurodegenerative disease, with powerful genetic tools and behavioural assays. This led me to seek a PhD where I can further explore my interest and increase my knowledge in Drosophila research and neurodegeneration.
Fanila Shahzad
Durham University
Supervisors: Dr David Doupe and Dr Laura Greaves
Transcriptional regulation of intestinal stem cell ageing
Project Description: Declining intestinal function is an important contributor to poor health in ageing. The epithelium that lines the intestine is constantly turned over throughout adult life, as cells are lost from the surface and replaced by the proliferation of stem cells. These adult tissue stem cells must be tightly regulated as loss of homeostasis can lead to tissue failure and risk of disease.
This project will characterize the importance of transcriptional regulators in epithelial maintenance and age-related loss of homeostasis. The student will use the intestinal stem cells of the fruit fly, Drosophila melanogaster, as a simple model system and employ a range of advanced genetic, genomic, molecular and microscopy approaches to characterize key regulators of gene expression and chromatin states.
NLD Research Thematic Areas: Regenerative Biology, Stem Cells and Neuroscience, Ageing, Diet and Health
Personal Background: I gained a BSc in Biomedical Sciences from the University of Bradford and recently gained an MPhil in Translational Biomedical Research from the University of Cambridge. During my academic career, I developed an intrinsic and unwavering motivation to pursue a career in stem cell research. Age-related changes in the intestinal epithelium of mammals remain understudied. I strongly believe that conducting innovative and interdisciplinary research on intestinal stem cells aging, that is readily translatable is vital to advancing the research, study and clinical benefit. During my PhD, I would like to utilise the skills gained from my past experiences to explore further and gain a deeper understanding of the importance of transcriptional regulators in epithelial maintenance and age-related loss of homeostasis. Using the fruit fly, Drosophila melanogaster, as a model organism to characterize key regulators of gene expression and chromatin states, I hope to gain in-depth knowledge into the characterization of intestinal stem cells aging, to expand this body of work and to develop therapeutic approaches based on a greater understanding of intestinal stem cells aging.
Gabrielle Ecclestone
University of Liverpool
Supervisors: Dr Niall Kenneth, Prof Jonathan Higgins and Prof Claire Eyers
Linking the unfolded protein response to oxygen sensing - A phosphoproteomic approach to identify novel substrates of the ER kinase PERK
Project Description: PERK is a kinase residing in the endoplasmic reticulum with a critical role in the unfolded protein response (UPR), a process by which cells stop protein synthesis and clear accumulations of misfolded proteins. Aberrant PERK signalling is associated with a number of age-related diseases such as cancers and neurodegenerative disease. Recent work has shown a role for PERK in the regulation of the hypoxia response dependent on hypoxia-inducible factor (HIF) signalling, but few direct substrates of PERK have been identified and the pathway underlying this link remains unclear. Through a combination of mass spectrometry and CRISPR experiments, this project aims to uncover novel PERK substrates and determine their roles in both the UPR and HIF response to improve our understanding of the interplay between these processes.
NLD Research Thematic Areas: Ageing, Diet and Health
Personal Background: I completed an Integrated Master’s in Biochemistry at the University of York in 2021. My main research interest is cell signalling, particularly kinase-dependent phosphorylation. For my Master’s project, I performed bioinformatic analyses on data gathered in yeast to uncover potential regulators of the trafficking of cell surface proteins. Prior to this, I undertook an internship at the Francis Crick Institute, where I helped validate putative substrates of the psychiatric risk kinase TNIK.
Hannah Coghlan
University of Liverpool
Supervisors: Dr Ian Copple, Prof Francesco Falciani and Mr Dominic Williams
Unravelling species differences in stress responses to inform the selection, and reduce the use, of animals in preclinical drug safety testing
Project Description: To ensure the safety of a new drug, preclinical investigations are often performed using a number of different model species including monkeys, dogs, rats, mice and pigs. Our understanding of the physiological similarities and differences between these species and the intended recipients of the drug – i.e., humans – inform the selection of relevant preclinical models. An important consideration is the ability of a species to sense and adapt to chemical insult via activation of one or more stress response pathways that exist to combat stresses such as reactive oxygen species or protein misfolding. However, despite the importance of this topic, it remains relatively unexplored. Recent evidence has uncovered differences between the basal and inducible activity of the Nrf2 stress response pathway between humans, rats and mice, indicating that inter-species differences do exist. Therefore, this project aims to investigate the differences in sensitivity and activity of the different stress response pathways between humans and various preclinical animal species to establish the translatability of preclinical drug toxicity studies. It is hoped that this research will support the refinement, and ultimately the reduction, of animal use in drug research. Further, this can help ensure that the animals selected during drug safety studies appropriately represent human physiology, improving human health.
NLD Research Thematic Areas: Systems Biology and Technology Development, Regenerative Biology, Stem Cells and Neuroscience
Personal Background: I have recently gained my MBiolSci in Pharmacology from the University of Liverpool. My interest in drug toxicity was sparked during my summer studentship at the Wolfson Centre for Personalised Medicine studying the pharmacogenetics of HIV drug toxicity; my dissertation research focused my interest on how the body responds to such toxicity through the Nrf2 stress response pathway. During my master’s project, which I conducted whilst working in the pharmaceutical industry, I developed an appreciation for the regulatory and testing processes that drugs go through to ensure their safety. I am excited to build upon my knowledge and skills during my PhD, which I hope will assist researchers in making informed decisions during drug development, improving the safety of new medicines.
Ianthe Doumas Calder
Durham University
Supervisors: Dr Tim Hawkins, Prof Boguslaw Obara, Dr Arto Maatta and Dr Adam Benham
Mapping the dynamics and regulation of the skin cell cytoskeleton during ageing
Project Description: Cytoskeletal changes are associated with skin fibroblast ageing and responses to chemical and mechanical stress. In this multi disciplinary project, we will use state of the art bioimaging technologies, including super resolution microscopy and bespoke analytical tools, to define the spatial and temporal organisation and dynamics of the fibroblast cytoskeleton during ageing. We will generate age-related network signatures through bioimage informatics to obtain maps for early ageing that can be investigated with various compounds. The project stems from a collaboration between cell biologists at Durham University and data scientists at Newcastle University, working together to deliver novel discoveries in the Biosciences. The project is also in collaboration with international industrial partner Procter & Gamble, who will provide training during a placement at the P&G central labs in the USA.
NLD Research Thematic Areas: Systems Biology and Technology Development, Industrial Biotechnology (IB), Synthetic Biology and Structural Biology, Ageing, Diet and Health
Imogen Garner
Newcastle University
Supervisors: Dr Jon Marles-Wright, Dr Karrera Djoko and Dr Kevin Waldron
Dissecting the role of a membrane-associated bacterioferritin complex in Neisseria gonorrhoeae
Project Description: Iron is a vital cofactor for many enzymes, and bacteria must ensure that they have an adequate supply of this essential nutrient. Upon infection by microorganisms, the animal host innate immune system typically reduces the availability of iron. In response, bacteria activate pathways for metal import, metal sparing, or metal storage to avoid stress from metal starvation. This competition for metals is termed “nutritional immunity”.
Ferritin proteins are the primary iron stores in all kingdoms of life, they act to oxidise and sequester iron in a bioavailable mineral form within a hollow protein cage. Some bacteria possess heme-binding bacterioferritins, which allow the rapid mobilisation of stored iron through electron transfer via the heme group.
This project focuses specifically on a membrane associated bacterioferritin complex from the Gram-negative pathogen Neisseria gonorrhoeae. This pathogen has been identified as a “superbug”, with multiple strains and isolates that have become completely resistant to all last-line antibiotics.
NLD Research Thematic Areas: Industrial Biotechnology (IB), Synthetic Biology and Structural Biology
Personal Background: I have a BSc in Natural Sciences from the University of East Anglia, in which I majored in Biochemistry. As part of my degree, I spent a year at the Technical University of Denmark where I studied more specific courses in protein chemistry and bioinformatics. This culminated in a short computational project looking at the structures of different human taste receptors. As a result, I wrote BSc dissertation on the structure-function relationships of the human umami taste receptor. I submitted both projects to the Global Undergraduate Awards where they were judged to be in the top 10% of entries in the Life Sciences category, each earning a Highly Commended award. I'm excited to start my PhD and gain more practical skills when working with proteins in vivo and in vitro.
James Evans
Durham University
Supervisors: Dr Vincent Croset and Prof Alistair Darby
Transcriptional control of learning and memory
Project Description: This project will use Drosophila melanogaster to explore the role of Activity Regulated Genes (ARGs), whose expression rapidly increases in response to neuronal activity. These genes often encode transcription factors which coordinate synaptic function, cellular transport, signal transduction, or plasticity. These processes are essential for memory, and a better understanding of how they are regulated could provide invaluable insights about the molecular mechanisms driving learning, and the consolidation and retrieval of memories.
The research will focus on ARGs expressed in memory neurons. I will investigate how learning shifts their expression across neuronal subtypes, and how this influences memory performance. Using ChIP-seq, I will analyse how these genes interact with DNA to identify what genes they control in different contexts.
Circuits of learning and memory have been extensively described in the fly. A full connectome, single-cell transcriptome atlases, and a host of tools to precisely manipulate genes and circuits are available, providing a unique opportunity to address the links between gene expression and behaviour, at a resolution that would be impossible to achieve in other organisms.
NLD Research Thematic Areas: Systems Biology and Technology Development, Regenerative Biology, Stem Cells and Neuroscience
Personal Background: I originally have a background in art, and was always interested in consciousness, behaviour, emotions and why people do the things they do, especially in the context of memory. I found the mix between art and psychology interesting, but decided to study biology as I wanted to know what was happening in the brain at a cellular and molecular level. My undergraduate degree was in Biomedical Science, with my sandwich/placement year at Cardiff University researching translational regulation in the germline and soma of Drosophila melanogaster. I then undertook a research masters in Genetics, using Caenorhabditis elegans to understand the control of eating and sleeping behaviours. I'm now back to flies, happy to research the cellular and molecular mechanisms of learning and memory! Outside of science I enjoy outreach work, singing, hiking, and generally being outside. So if you find me up a tree singing about how to widen participation in HE, come join!
Katherine Sanders
Newcastle University
Supervisors: Dr Adam Wollman and Dr Nordine Helassa
Next generation infra-red glucose biosensors
Project Description: Glucose is a key metabolite for microorganisms, the most important energy source in animals and is a key product of photosynthesis in plants. In order to fully understand energy metabolism, homeostasis and photosynthesis, a robust tool to accurately map glucose concentrations in living organisms would be transformational. The electrochemistry behind patient glucose monitoring devices is bulky, invasive and unsuitable in vivo. Standard glucose uptake assays using radiolabelled glucose are slow, low resolution and insensitive, working only in bulk tissues or cultures, requiring radioactive material. Fluorescent glucose biosensors, fluorescently labelled molecules which bind glucose resulting in a change in output fluorescence intensity or colour have shown great promise in live microorganisms and cells. However, these applications are currently limited by the use of visible wavelength light, readily absorbed by tissues. Recent advances in proteins which fluoresce in the infrared, where tissues are relatively transparent, could provide the answer to develop the next generation of glucose biosensor.
My project aims to design, express and purify a modified glucose biosensor based on past designs, utilising infrared fluorescent proteins. The sensitivity and photophysics of the sensor will be characterised in vitro and in vivo using yeast and mammalian cell lines. These biosensors will allow for real-time glucose monitoring in whole tissues and organisms, meaning it would have multiple applications from microorganisms to glucose homeostasis in animals. There is also the potential for infra-red glucose biosensors to be useful in the clinic as a less invasive patient glucose monitoring tool.
NLD Research Thematic Areas: Systems Biology and Technology Development
Personal Background: I gained my BSc in Biomedical Science at the University of Sheffield then immediately went on to work as a Research Assistant at Oxford University’s Oxford Vaccine Group for two years. I helped deliver clinical trials for vaccines against diseases such as Whooping cough and Meningitis and from the start of the COVID-19 pandemic I worked on the Oxford-AstraZeneca vaccine clinical trial which led to the rapid licensure and deployment of the vaccine globally.
I have a long-standing interest in Diabetes and so the potential applications of this PhD project for glucose research and even patient application are exciting.
In my spare time I enjoy surfing and paddleboarding on the North East coast.
Laura Dobby
Newcastle University
Supervisors: Dr Henrik Strahl von Schulten, Dr Gary Sharples and Dr Kevin Waldron
Uncovering the killing-mechanism of bactericidal antibiotics
Project Description: Is there a parallel killing mechanism shared by cell-wall targeting antibiotics and aminoglycosides? Preliminary data has demonstrated when Bacillus subtilis are treated with cell wall-targeting antibiotics, they lose viability far prior to cell lysis, indicating a killing mechanism which precedes lysis. It has also been demonstrated that cell wall-targeting antibiotics and the aminoglycoside Kanamycin, both induce bacterial membrane depolarisation. Potentially, this may be indicative of a shared bactericidal mechanism between the two classes of antibiotics despite their different cellular targets. However, the pleiotropic disturbances caused by membrane depolarisation in response to bactericidal antibiotics; particularly aminoglycosides, remains poorly informed. My project will build upon preliminary data to uncover the bactericidal mechanism of aminoglycosides in the nosocomial pathogen Staphylococcus aureus, and the soil-dwelling bacterium Bacillus subtilis, by investigating the role of: (1) reactive oxygen species (ROS), (2) the DNA damage response, and (3) transcription and translation (ppGpp).
NLD Research Thematic Areas: Ageing, Diet and Health
Personal Background: I undertook my BSc Biochemistry degree at Newcastle University, during which I worked as a laboratory technician within a eukaryotic microbiology lab (focussing on the pathogen Candida albicans). My time as a laboratory technician sparked not only a love for microbiology, but I could also envision myself going into research. This compelled me to undertake a summer project, which was kindly funded by the Microbiology Society, and focussed on an in-silico analysis of the bacterial DNA replication initiator DnaA. As a result of my work, I was given the opportunity to present a poster of my research at the Microbiology Society annual conference 2021! Having graduated in summer 2021, I achieved a 1st class honours degree in BSc Biochemistry, whom I was ranked 3rd across the cohort. I am now undertaking a BBSRC-DTP studentship in the Centre for Bacterial Cell Biology under the supervision of Henrik Strahl!
Maria Birgaoanu
Newcastle University
Supervisors: Prof Konstantinos Stellos, Dr Aditi Kanhere, Prof Stefan Przyborski and Dr Aikaterini Gatsiou
Understanding the epitranscriptional rules of escaping detrimental innate immune activation
Project Description: A derailed innate immunity underpins the pathogenesis of many diseases including autoimmune disease, cancer, cardiovascular disease, and aging. Our cells are equipped with specialized tracking systems that prevents them from being in a constant state of alert due to an aberrant activation of our immune system. These tracking systems have been developed to sense perfectly matched long double-stranded RNAs (long-dsRNAs) which are immediately recognized as intruders because they are usually indicative of a virus presence, and therefore they trigger this persistent immune response. If these surveillance systems do not work properly, our cells will suffer from an inflammatory overload and eventually will be compromised. A modification on adenosine (A) RNA nucleotides that converts A into inosine (A-to-I RNA editing) on these long-dsRNAs has been shown to be the key for this fundamental biological process. We found that Adenosine deaminase acting on RNA-1 (ADAR1), which catalyses A-to-I RNA editing, is highly expressed in endothelial cells which line the inner layer of our blood vessels spanning our body. Importantly, we found that ADAR1 prefers indeed to edit those long-dsRNAs in endothelial cells with functional consequences like development of inflammatory diseases. We now want to know what happens next and how exactly ADAR1-RNA editing does that?
To address this question, we will employ a variety of traditional but also more advanced and innovative RNA and cellular biology technologies of tomorrow such as epitranscriptomics, stem cells and genome editing approaches to study this RNA modification, that pioneered the emerging field of epitranscriptome.
NLD Research Thematic Areas: Systems Biology and Technology Development, Regenerative Biology, Stem Cells and Neuroscience, Ageing, Diet and Health
Meagan Hennessy
University of Liverpool
Supervisors: Dr David Turner, Prof Neil Perkins and Prof Mike White
How does NF-𝜅B influence cell fate decisions during early mammalian development?
Project Description: Nuclear Factor kappaB (NF-𝜅B) signalling has long been studied for its role in inflammation and proliferation in the adult organism. However, recent research suggests that NF-𝜅B signalling may act to guide differentiation during early development. The complexity inherent in NF-𝜅B pathway provides a high degree of flexibility in directing a precise cellular response to specific signals amidst a heterogenous environment. While this would serve the pluripotent cells of the early embryo well in directing differentiation and the generation of the body plan in such an environment, the exact mechanism of NF-𝜅B signalling in early development remains undefined.
We aim to characterise the role NF-𝜅B pathway plays in maintaining and directing the exit of mouse embryonic stem cells from pluripotency. By coupling bulk cell techniques with single cell analyses we hope to outline the role of NF-𝜅B signalling during cell fate transitions and determine if and how fate decisions are regulated by NF-𝜅B dynamics. Doing so will not only address how a previously unexplored signalling pathway mitigates the cellular exit from pluripotency but will also allow us to integrate this pathway into the network of known regulatory mechanisms to further both our understanding and control of the differentiation process.
NLD Research Thematic Areas: Systems Biology and Technology Development, Regenerative Biology, Stem Cells and Neuroscience
Personal Background: I am primarily interested in understanding how cell fate decisions can differ between neighbouring cells. A single cell grown in a defined culture medium in theory should reliably produce a consistent cell type. However pluripotent cells either in the laboratory or in nature are rarely found in such isolation. Understanding how different cells in close contact to one another can differentiate readily into different cell types requires a focus on understanding how a single cell influences and is influenced by the greater part of the whole organism it inhabits.
I received my BSc in Molecular Cell and Developmental Biology from UCLA and my MRes in Regenerative Medicine from the University of Bath. I am excited to begin my PhD project which will allow us to study a previously studied pathway in a previously unstudied environment (i.e early development) while also allowing us to compare the regulatory behaviours of a single cell amidst a multicellular unit.
Megan Rigby
University of Liverpool
Supervisors: Dr Mark Morgan and Prof Matthias Trost
Ubiquitylation Dynamics in Adhesion Complexes: Impact on Cell Migration and the Transcriptional Landscape
Project Description: Adhesion complexes are dynamic structures used by cells to interpret and respond to their extracellular environment. Adhesion complex signalling contributes to almost all biological processes in multicellular animals and disruption drives a wide range of diseases, particularly cancer. Integrin receptors in adhesion complexes control how mechanical forces from the extracellular environment are transmitted across the membrane to control cell migration and transcription. By employing proteomic approaches, we can dissect the molecular complexity within the network of proteins recruited to integrins (the “adhesome”). We have evidence that many molecules that regulate ubiquitin are recruited to the adhesome. The ubiquitin system comprises a complex range of enzymes and polypeptides that regulate protein stability and signalling to co-ordinate biological processes. We now want to investigate how the “ubiquitin code” dynamically regulates adhesion complexes, cell migration and integrin-dependent transcription.
NLD Research Thematic Areas: Systems Biology and Technology Development
Personal Background: I have a BSc in Biomedical Sciences from Newcastle University, completing research projects specialising in prostate cancer. Recently I have completed an MRes in Molecular Oncology at the University of Liverpool, to progress my previous research experience. This particularly advanced by interest in the impact of ubiquitination upon transcriptional regulation in oncogenesis. I am really looking forward to building upon the skills I have previously gained, to explore how ubiquitination regulates adhesion during my PhD.
Mukilan Suresh
Newcastle University
Supervisors: Prof Jenny Read, Dr Olena Riabinina, Prof Andrew Trevelyan and Dr Damon A Clark
Imaging the neural mechanisms of distance estimation in insects
Project Description: Stereopsis is the ability to perceive distance using small differences between the images seen by the two eyes. Long thought to be a complex ability confined to “higher” animals such as primates, it has now been identified in species as diverse as mice, owls, toads and cuttlefish. It has so far been demonstrated in only one type of insect, the praying mantis. This raises fascinating questions about how tiny insect brains achieve stereopsis. Notably, we do not know how they solve the fundamental problem of “stereo correspondence”.
My lab has previously worked on behavioural aspects of mantids with an innovative “virtual reality” setup and neurophysiological work using microelectrodes within the mantid brain. Now, I will be utilizing 2 - photon imaging to visualise the mantid brain in action, using Ca2+ biosensors. I will also attempt to create transgenic mantids in which specific neuronal populations express Ca2+ sensors intrinsically. Finally, I will construct mathematical models summarising the behaviour of these neurons.
Our results will inspire robotic approaches for visual perception machines, as well as shedding light on our own human perception. The results will be of interest well beyond insect neuroscientists, since they will reveal to what extent different species have evolved their stereo vision.
NLD Research Thematic Areas: Regenerative Biology, Stem Cells and Neuroscience
Personal Background: I have an undergraduate Biotechnology engineering degree from India, where I was working with Aedes Aegypti mosquitos on how they are susceptible to DENV2 virus. For my master’s degree in Italy, I was working with Apis mellifera bees to see how their aggression is affected by the smell of rain (Geosmin). I am keen on exploring interdisciplinary fields that explore the intricate life of insects.
Pei Cing Ng
University of Liverpool
Supervisors: Prof Luning Liu, Dr James Johnson, Dr Thomas Howard and Dr Jon Marles-Wright
Biosynthesis and Reprograming of Bacterial Organelles
Project Description: Bacterial microcompartments (BMCs) are organelles which perform cell compartmentalisation in bacteria, a phenomenon previously thought to be restricted to eukaryotic cells. Like viral capsids, they consist of thousands of protein subunits which self assemble into a polyhedral shell. Previous research have highlighted BMCs as a suitable target for biotechnological applications: they self-assemble, packaging core enzymes in their centre; they allow specific substrates and metabolites to pass through their selectively permeable shell; they consist of modular shell proteins, allowing a mix-and-match approach in cargo targeting and shell design.
Carboxysomes as the only currently known anabolic BMC encapsulate RuBisCO for enhanced carbon fixation in cyanobacteria and certain chemoautotrophic bacteria. My project aims to further dissect the molecular biogenesis of carboxysomes, primarily using techniques in microscopy and molecular genetics. I will then aim to build upon this knowledge in the design of synthetic biology tools to bioengineer carboxysomes into a bespoke nanoreactor with new catalytic activities.
NLD Research Thematic Areas: Agriculture and Food Security, Systems Biology and Technology Development, Industrial Biotechnology (IB), Synthetic Biology and Structural Biology
Personal Background: I came from Malaysia to study for a BSc in Biochemistry and Microbiology at the University of Sheffield. There, I conducted scientific research for the first time in a summer project focussed on understanding pigment biosynthesis in photosynthetic bacteria using molecular genetics. I then decided to further explore my research interests in molecular photosynthesis in my third year project, where I learnt how to use atomic force microscopy to investigate the molecular basis of photosynthetic electron transfer. I am excited to be moving into the 'dark reactions' of photosynthesis for my PhD, starting anew in a different city, making new friends and taking advantage of all the opportunities being a doctoral student can bring! I generally enjoy bopping along to music, being in nature and having interesting conversations with people.
Polly Burton
Newcastle University
Supervisors: Dr Louise Reynard, Dr Simon Tew and Prof David Elliott
Investigating how alternative splicing processes affect cartilage biology from development to old age
Project Description: Alternative splicing (AS) and alternative polyadenylation (AP) are post-transcriptional processes that affect mRNA, allowing for the generation of multiple different protein isoforms from a single gene, thus increasing the diversity of functions of the transcribed proteins in a given tissue. The dysregulation of AS and AP has already been shown to contribute to age-related pathologies, including cardiovascular disease and cancer, with studies also showing that the number of alternatively spliced genes increases with age. Cartilage in particular is a tissue that is associated with various age-related diseases, such as osteoarthritis.
Using various molecular and cell-based techniques combined with in silico analysis, this project will explore cartilage development, health, and age-related dysfunction on a global transcriptome level. It aims to characterise alternative mRNA isoforms across the lifespan, and to examine the contributions of AS and AP to the fundamental biological processes involved in cartilage biology. As these molecular mechanisms have already been deemed essential to cartilage development and differentiation, gaining knowledge of how they alter the transcriptome from embryonic stages to old age would provide insight into how to develop therapeutics to target cartilage age-related dysfunction.
NLD Research Thematic Areas: Regenerative Biology, Stem Cells and Neuroscience, Ageing, Diet and Health
Personal Background: I graduated from King's College London with a BSc in Molecular Genetics, completing my dissertation in the Habib lab at the Centre of Stem Cells and Regenerative Medicine. As part of my degree, I undertook a placement year in the Developmental Genetics department of the Max Planck Institute for Molecular Genetics. My research project was focused on improving the recapitulation of embryonic tissue morphology in gastruloids, a post-occipital model of a gastrulating embryo cultured in vitro, which contributed to my intrigue for tissue engineering and developmental biology. My degree pushed me to undertake a project that could allow me to continue pursuing my interest for molecular genetics, whilst also allowing for me to broaden both my in vitro techniques and bioinformatics skills.
Raghavendra Kudinalli Nagaraj
University of Liverpool
Supervisors: Dr Vicencio Oostra, Dr Miguel De Lucas and Prof Ilik Saccheri
Architecture and evolution of gene regulatory networks underlying environmental responses in butterflies
Project Description: This project investigates how African butterflies tune their morphology, behaviour and life cycle to wet and dry seasons. This adaptation—‘phenotypic plasticity’—is widespread as almost all environments show variability, in particular between seasons.
While we know a great deal about why plasticity is important in nature, we know much less about how plastic responses are accomplished during development. What are the genes and pathways that sense the environment and produce a different phenotype when the environment changes? How do these genes interact in gene regulatory networks? How have these networks evolved when species invade new habitats or are faced with environmental change? How does plasticity affect future adaptation, for instance to climate change?
In order to fill this gap, we use an established system that combines ecological relevance, experimental tractability and genomic resources—African Bicyclus butterflies. Species have repeatedly evolved plasticity in wing pattern, behaviour and life cycle upon invasions of seasonal savannahs from forests. Laboratory experiments have revealed Ecdysteroid hormone signalling as a key switch between developmental pathways leading to alternative adult phenotypes. However, the mechanistic relationship between this switch and environment-sensitive GRNs is unknown, as are the evolutionary origin and dynamics of these GRNs.
NLD Research Thematic Areas: Agriculture and Food Security, Systems Biology and Technology Development
Personal Background: I have an M.Sc in Genomic Science from the Central University of Kerala, India. I have been researching on butterflies for the past 5 years and my observations supported by various courses taught at my master’s inspired me to comprehended how butterflies are better model systems to elucidate various phenomena of eco-evo-devo to address long-standing questions in population history and evolution. I developed a keen research interest surrounding the developmental plasticity in butterflies, particularly the striking adaptive seasonal plasticity leading to polyphenism, diapause, and behavioural changes. The seasonal plasticity occurs within a regulatory network of genetic effects influenced by the role of alternative splicing, transcription factors, post-transcriptional regulatory mechanisms and the interaction of various other elements. The perplexing fact that the nature of these networks can facilitate or retard potential evolutionary responses unless the responses are genetically assimilated compelled me to go for a career in scientific research.
I am highly excited about my PhD project as it is a multidisciplinary project which covers evolutionary biology, developmental and molecular biology, and genomics. It employs a broad range of experimental and computational techniques that foster integrative approaches to biology and provides me with training by supervisors from different backgrounds.
Rebecca Price
University of Liverpool
Supervisors: Dr Jill Madine, Prof Dan Rigden, Prof Michael Taggart
Searching for amyloid forming bacteria using bioinformatics and experimental approaches
Project description: Amyloid proteins are biologically fascinating, with many aspects of their formation and interaction poorly understood, and are intimately involved in a variety of human diseases. Typically regarded as the result of pathological misfolding, for some proteins (mainly bacterial proteins) amyloid is the normal functional structure. Recent work shows that these proteins, found on the surface of gut bacteria, can interact with host proteins that are also capable of (mis)folding into an amyloid state with potential relevance for conditions such as Parkinson’s and Alzheimer’s diseases. At present, only a few bacterial functional amyloid proteins have been characterised and much remains poorly understood about their interaction with host proteins. This project aims to discover new families of bacterial function amyloid proteins and probe their interaction with host proteins, cells and systems. Bacterial functional amyloid proteins adopt a B-helical structure and are built of repeating sequences with each repeat contributing a number of layers of the B-helix. The bioinformatics discovery phase of the project therefore centres on revealing unsuspected repeat proteins, then deploying state of the art ab initio structure prediction methods, as exemplified by Google AlphaFold, to test whether they adopt a B-helical structure. These methods have made huge advances in recent years and have broad applicability across the protein universe: the successful applicant will therefore gain hugely valuable experience in this fast-moving area.
Following identification of potential candidate proteins will be recombinantly expressed and ability to form amyloid and interactions with host proteins assessed using a range of experimental techniques. Effect of microbial proteins on cell biological function will be probed at the second institution by studying the effect on cell signalling pathways in smooth muscle and endothelial cells.
This project will provide training in biochemical and biophysical techniques and cell signalling to complement novel bioinformatics skills. The aims of this project are to enhance understanding of the interactions between bacterial and host proteins, along with increased knowledge of the process and impact of novel structural re-arrangements that can occur upon protein-protein interaction. This knowledge has the potential to understand the role of potentially pathogenic bacteria introduced via the gut microbiome or infection in a range of health and disease situations.
Samrajni Banerjee
University of Liverpool
Supervisors: Prof Malcolm Jackson, Dr David Wilkinson, Prof Anne McArdle, Dr Daryl Shanley
Mitochondrial network disruption as a final common pathway in the age-related decline of multiple tissues
Project Description: There is increasing evidence that ageing-related decline of multiple tissues is associated with a decline in mitochondrial functions such as reduced capacity for energy generation, abnormal cell calcium handling, increased reactive oxygen species generation and increased apoptotic signalling. The causes of these changes are unknown, but it is known that within cells mitochondrial form a complex network. Under physiological conditions, mitochondrial fission and fusion events occur in a balanced frequency to maintain not only the size and shape of the mitochondrial network, but also its gross distribution. Increased mitochondrial ROS, low respiration rates, aberrant calcium handling and increased apoptosis are known to be consequences of the reorganisation of the mitochondrial reticulum via increased fission and reduced fusion. The project will utilise electron microscopy, various biochemical assays to understand how disruption of the cellular mitochondrial network might be a prerequisite for derailed mitochondrial functionalities in aging tissues.
NLD Research Thematic Areas: Regenerative Biology, Stem Cells and Neuroscience
Personal Background: I have a BSc degree in Biochemistry and a MSc in Biotechnology specialising in disease biology. I developed a fond interest in biochemistry during my undergraduate studies and since then have looked forward to understanding fundamental alterations at a cellular level that cause dysfunctionality or disease. I have gained skills in biochemical techniques, molecular biology techniques and genetic engineering. I am looking forward to do a PhD in understanding the primary triggers of aging.
Sean Farrell
Durham University
Supervisors: Dr Noura Al-Moubayed, Dr Peter-John Mäntylä Noble, Dr David Singleton and Dr Gina Pinchbeck
Can hybrid (unsupervised and supervised) text-mining methods be used for efficient, accurate, automated annotation of companion animal electronic health records to better understand drivers of antibiotic use in veterinary care?
Project Description: Antimicrobial resistance (AMR) is a critical challenge for human and animal health that requires a coordinated endeavour across the disciplines of clinical and data science. My project seeks to embody the interface between these fields to understand the features and signals that might be available in a large clinical dataset of companion animal clinical records and to develop and apply cutting-edge machine-learning methodologies to derive important insights. To combat AMR, we need to understand the factors that influence antimicrobial prescription by veterinary clinicians, the dataset contains well over 7 million records which is far beyond the scope of manual reading and hence the importance of novel data science strategies such as natural language processing. Capitalising on these such large datasets may hold the key to reducing antimicrobial usage and ultimately to stagnate the development of AMR.
NLD Research Thematic Areas: Systems Biology and Technology Development
Personal Background: Whilst studying Biomedical Science BSc at the University of Kent, I worked extensively at the University of Liverpool within this Veterinary Bioinformatics laboratory at SAVSNET using the same datasets I will be using in my PhD, for other projects such as fleas and myxomatosis leading to eventual publications. These projects highlighted to me the versatility of data in the pursuit of uncovering unknown risk factors that we hope will have lasting impacts within the veterinary practices. My continual interest in data science inspired my bioinformatics-based undergraduate dissertation analysing empirical antimicrobial usage within hospitalised COVID-19 patients on their gut microbiome, bringing to light the grave AMR situation. This PhD will continue my data science journey at Durham University into advanced bioinformatic methodologies against the increasingly concerning AMR.
Tim Bell
Newcastle University
Supervisors: Prof Akane Kawamura, Prof Shoumo Bhattacharya, Dr Ehmke Pohl and Dr Steven Cobb
The molecular basis of how the chemokine network is targeted by evasin proteins from tick saliva
Project Description: Chemokines are small secreted proteins that are major drivers of inflammation, functioning via binding to GPCRs to recruit immune-inflammatory cells to damaged tissues. Ticks secrete small proteins called evasins, in saliva, that have the ability to bind and neutralise multiple chemokines, thus disabling the host chemokine network. This property allows ticks to feed for days without detection. Evasins have been shown to have potent anti-inflammatory effects in preclinical models, including in myocardial infarction and plaque inflammation. Over 40 tick evasins from multiple tick species have been identified to date, all with broad and promiscuous chemokine binding properties.
We aim to study the biochemical properties of the interaction interfaces between evasins and chemokines using chemical and structural biology techniques. Protein fragments will be employed to understand the molecular basis of the multi-chemokine binding properties of evasins, and to investigate how evasins neutralise chemokine function. We also aim to understand more about the selectivity of these interactions through modification of fragments/proteins by chemical synthesis, expanding our rationale for therapeutic development.
NLD Research Thematic Areas: Industrial Biotechnology (IB), Synthetic Biology and Structural Biology, Ageing, Diet and Health
Personal Background: I have recently graduated from the University of York with a BSc in Biochemistry. During my degree I completed a year in industry at the Institute of Cancer Therapeutics working on peptide prodrugs and investigating molecular interactions involved in metastatic cancers. For my final-year research project I worked on locating and correcting erroneous glycan structures found the PDB using computational methods. Having worked across biochemistry, medicinal chemistry, structural biology and computation I have found I enjoy interdisciplinary science and look forward to exploring these themes in my project.
Zoe Catchpole
Zoe Sheaf
Newcastle University
Supervisors: Dr Katrina Madden, Dr Akane Kawamura and Prof Sonia Rocha
Interrogating the role of KDM5 in inflammation
Project Description: Lysine demethylases (KDMs) play key roles in a wide range of biological processes, including regulating gene expression and altering protein function. In particular, the Jumonji C (JmjC) domain sub-family of KDMs plays a role in the cell’s response to oxygen levels, and are implicated in various pathological conditions, including cancer, immune disorders and neurodegenerative disease. Although recent work has generated a considerable amount of detail about how these enzymes work, interrogating the role of each member of the JmjC KDM family in ordinary cell signalling remains challenging due to a lack of selective and potent small molecule chemical tools. Therefore, the aim of my project is to develop novel, selective chemical tools for KDM5 and use these to elucidate more about its role in cell function, oxygen sensing and inflammation. The project will involve design and synthesis of chemical tools, testing in KDM-relevant assays, and then testing in cell-based assays studying cell function and inflammation.
NLD Research Thematic Areas: Systems Biology and Technology Development, Regenerative Biology, Stem Cells and Neuroscience, Ageing, Diet and Health
Personal Background: I graduated from the University of York in 2021 with an integrated Master’s in Chemistry, with Biological and Medicinal Chemistry. In the final year of my degree I completed an industrial placement at Sosei Heptares within the medicinal chemistry team, focussing particularly on the design and synthesis of chemical probes targeting G protein-coupled receptors. This sparked a keen interest in chemical biology and the development of chemical probes, and I am looking forward to carrying out further research developing small molecule chemical tools throughout the course of my PhD. I am also excited to conduct interdisciplinary research, and expand my scientific experience beyond medicinal chemistry by utilising these tools subsequent assays.