MVLS DTP

Supervisors:

Alberto Sanz, Institute of Molecular, Cell and Systems Biology

Julia B Cordero, Institute of Cancer Sciences

PhD project summary:

Ageing is one of the last mysteries in biology remaining to be solved. Besides, population ageing is one of the main problems we must confront as a society during this century. To solve both the mystery and problem of ageing, we need to understand the fundamental mechanisms that drive it. This project offers a unique opportunity to participate in the quest for solving the ageing dilemma guided by a diverse and committed supervisory team. You will dissect mitochondria's role in determining lifespan during development and adulthood. We have discovered a window of opportunity occurring during animal development when mitochondrial function determines the actual duration of adult lifespan. You will characterise this new phenomenon in detail by dissecting the metabolic changes triggered by mitochondria and developing strategies to reprogramme adult cells restoring expected lifespan. To achieve your goals, you will learn to manipulate mitochondrial function using state-of-the-art genome editing technology. Furthermore, you will master how to measure mitochondrial function by diverse techniques ranging from classical biochemical assays to advanced confocal microscopy imaging. Finally, you will receive exhaustive training to analyse big epigenomic/transcriptomic/proteomic/metabolomic data using statistics and machine learning and use this knowledge to reprogramme the metabolism of adult flies. 

Supervisors:
Prof William Stewart
Dr Donald Lyall
Dr Terry Quinn

PhD project summary:
Traumatic brain injury (TBI) is recognized asa major risk factor for a range of neurodegenerative diseases, including Alzheimer’s disease and chronic traumatic encephalopathy (CTE). This association has attracted particular attention in recent years through increased reporting of the specific, TBI related neurodegenerative pathology of CTE in autopsy examinations of former contact sports athletes. In parallel, epidemiological studies reveal high risk of neurodegenerative disease among former professional soccer players, and others. In this background, attention is turning to strategies to identify individuals most at risk of TBI related neurodegeneration, which will then permit targeted interventions to mitigate risk.“Defining imaging biomarkers of traumatic brain injury related neurodegeneration (Imaging TReND)” is designed to provide first insights into imaging signatures that might predict cognitive decline in individuals with a history of TBI exposure. To achieve this, Imaging TReND will access unrivalled research level clinical and linked imaging datasets to compare imaging studies in TBI exposed and non-exposed and their association with cognitive outcome. Experience from this analysis will then be applied to unique diagnostic datasets from former contact sports athletes and their matched general populations controls.

Supervisors:
Prof Jonathan Cavanagh
Dr Mick Craig

PhD project summary:
Depression is a mental health disorder with symptoms including low mood and anhedonia (loss of interest and pleasure), the latter being regarded as a key, but not unique, symptom of depression. Depression is common with a UK prevalence of 4.5%, and almost a fifth of adults report being diagnosed with depression at some point in their life. Depression has both environmental and genetic risk factors. Chronic inflammation is associated with depression, e.g. 20% of rheumatoid patients develop depression. Interestingly, in some patients, anti-inflammatory treatment can reverse the depression even before peripheral inflammation has resolved.

As yet, there is no established genetic mouse model of anhedonic depression. Using data from latest GWAS surveys, this project will incorporate the two genes that confer the highest risk of depression into a novel mouse model and determine whether these genes increase susceptibility to developing depression-like behaviour when experiencing chronic inflammation, with a particular focus on prefrontal cortex and its connections. Skills learned in this project will include patch-clamp electrophysiology, mouse behaviour and stereotaxic surgery. Neuroimmunology is an emerging field relevant to myriad brain diseases, so the successful student will be equipped with expertise needed to launch a successful career in this field.

Supervisors:

Kristina Kirschner, Institute of Cancer Sciences

David Ferenbach, University of Edinburgh

PhD Project Summary:

Senescence is cessation of proliferation and by a pro-tumorigenic secretome. Primary senescent cells can propagate secondary senescence to neighbouring cells. We showed that these two senescent populations differ in their gene expression and secretomes. We will investigate the role of stromal cell primary and secondary senescence in kidney cancer initiation, progression and resistance to chemotherapy.

Aim 1: Elucidate the role of primary and secondary senescence on tumorigenesis in-vitro.

We will sort primary and secondary senescent cells for co-culture with kidney cancer cell lines to test senescence impact on tumoral properties and response to chemotherapy.

Aim 2: Elucidate the role of primary and secondary senescence on tumorigenesis in-vivo.

We will co-inject senescent cell populations with kidney cancer cells into mice characterising tumours, their environment and their response to chemotherapy.

Aim 3: Test senolytics on primary and secondary senescence interacting with cancer cells in-vitro and in-vivo.

Senolytics drugs specifically eliminate senescent cells. In the previous in-vitro and in-vivo models, we will test if senolytics counteract the effects of primary and secondary senescence on cancer.

In conclusion, this project identifies responses of secondary and primary senescence to therapy and provides a rationale for using senolytics in cancer therapy.

Supervisors:

Monika Harvey, School of Psychology and Neuroscience

Cassandra Sampaio Baptista, School of Psychology and Neuroscience

Jesse Dawson, Institute of Cardiovascular and Medical Sciences

Terry Quinn, Institute of Cardiovascular and Medical Sciences

PhD project summary:

Post-stroke fatigue has significant implications for morbidity, disability and quality of life affecting between 25 to 85% of stroke survivors, with the variability depending on definitions used. It is persistent over time with significant consequences for post-stroke outcome, including failure to complete daily tasks, inability to participate socially, care for others and drive. It is associated with poorer physical health, later return to work and higher risk of death. Unfortunately, despite the pervasiveness of this symptom, at present, it is unknown why some stroke patients experience post- stroke fatigue while others do not.

In this PhD project we will investigate if fMRI resting state activity reflects post -stroke fatigue: The student will first run a pilot investigation on chronic stroke patients who either do or not suffer from post-stroke fatigue and establish if subjective trait and state fatigue measures are reflected in the decline/preservation of objective sustained attention measures, actigraphy and sleep patterns. In the main study, the student will then test if chronic stroke patients’ fMRI resting state is reflected in the decline (or preservation) of this fatigue, activity assessments.

The project combines a psychological approach mapping subjective and objective fatigue changes onto clinical neuro-imaging techniques. The overarching aim would be the testing of a new interdisciplinary methodological approach that should evolve into a guided therapeutic avenue for tackling post-stroke fatigue.

Supervisors:

Richard McCulloch, Wellcome Centre for Integrative Parasitology

James Cotton, Wellcome Centre for Integrative Parasitology

Jeziel Damasceno, Wellcome Centre for Integrative Parasitology

PhD Project Summary:

Leishmania are single-celled parasites that cause a collection of neglected infectious diseases affecting around 1 million people every year. Besides their biomedical importance, Leishmania are highly divergent from model eukaryotes, and as such have highly unusual molecular and cell biology. One aspect of this is that they cannot regulate transcription, so it is unclear exactly how they adapt their gene expression to challenges such as anti-parasitic drug treatment. One clue is that there is widespread genome variation, from local events involving changes in the number of copies of one or a few genes to variation in the number of chromosome copies. This so-called copy number variation (CNV) occurs at levels that would be pathological in other species. In this project, we will use modern CRISPR-based genome engineering to introduce barcoded antibiotic-resistance markers and track how the copy number of these loci varies in response to selection. We will then use this assay to assess how genes involved in DNA replication, repair and recombination influence CNV generation. The successful student will develop widely-applicable skills in modern molecular and cell biology such as design and implementation of CRISPR-Cas9, PCR, DNA cloning, cell culture, and microscopy, along with the bioinformatics and statistical skills to analyse these data that are also essential to a career in modern biomedical science.

Supervisors:

Rick Maizels, Wellcome Centre for Integrative Parasitology

Orhan Rasid, Institute of Infection, Immunity & Inflammation

PhD project summary:

Immunological memory is the defining feature of the mammalian immune system, underpinning vaccines and protective immunity. The dogma that only the adaptive immune system (B and T cells) is capable of acquiring immunological memory now has to be revised with accumulating evidence showing that innate immune cells from macrophages to NK cells can respond differently upon a secondary challenge. Innate lymphoid cells (ILCs), which are thought of as innate counterparts of T cells, have also recently been shown to be capable of mediating memory-like responses, however many unknowns remain. ILCs have a well-established role in response to infection, and helminth immunology is one of the areas where their actions are known to be of crucial importance, including that they contribute to secondary responses. Using mouse models of helminth infection, this project aims to study ILCs and other cells of the innate system in primary and secondary immune responses in order to define the properties of innate immune memory to helminths. The student will use cutting-edge cytometric, transcriptomic, epigenomic and imaging techniques to achieve these aims.

Supervisors:

Greg Weir, Centre for Neuroscience (School of Psychology & Neuroscience)

Carmen Huesa, Institute of Infection, Immunity & Inflammation

Andrew Cooper, Centre for Neuroscience (School of Psychology & Neuroscience)

PhD project summary:

Chronic neuropathic pain is a major public health problem, and there is a pressing need to develop more effective and specific treatments. Nerve damage induces changes in the somatosensory nervous system that result in pain. Excessive electrical activity of sensory neurons is key to the pain experienced, however, the environmental and cellular cues which drive this activity are not fully understood. A key feature of nerve injury-induced changes is up-regulation of immune cells that sensitise nociceptive neuronal circuits. Using a variety of cutting-edge molecular techniques, this project seeks to investigate how excessive sensory neuron activity shapes the immune response to nerve injury. Understanding such neuroimmune coupling has the potential to define new druggable targets and advance development of novel analgesic strategies. Experimental techniques to be used, include, RNA sequencing of immune cell populations, anatomical characterisation of transgenically/virally labelled sensory neurons and immune cells, induced pluripotent stem cell culture, and behavioural analysis. The project will provide the student with invaluable transferrable skills and a strong knowledgebase within the pain field, and will facilitate the development of a professional network that will support their future career.

Supervisors:

Filippo Queirazza, Institute of Health & Wellbeing

Marios Philiastides, Institute of Neuroscience and Psychology

PhD Project Summary:

Patients suffering from a first episode psychosis (FEP) will typically present with hallucinations, delusions and lack of insight. The mainstay treatment for these patients is an antipsychotic medication. Unfortunately, only around 55 – 70% of patients will respond to antipsychotics in the first 12 months. Early identification of treatment response is therefore crucial to curtail patients’ suffering, healthcare costs and improve long-term outcome. At present there is no clinical biomarker that helps predict treatment response. A novel and promising approach to biomarker discovery in psychiatry research is the development of theory driven biomarkers, that are embedded in the mechanisms underpinning core clinical manifestations of psychiatric illnesses. Here, we will use computational modelling and state-of-the-art brain imaging (fMRI) to illuminate the neurocomputational mechanisms underlying core psychotic symptoms such as auditory hallucinations and lack of insight in FEP patients. Crucially, we will capitalise on these mechanisms to classify response to antipsychotic medications at the individual level. To this end we will use advanced machine learning classification algorithms applied to neuroimaging data. Overall, this project involves computational modelling, advanced analysis of neuroimaging data and the use of state-of-the-art machine learning techniques, providing training in key skills for translational neuroscience and precision medicine.

Supervisors:

Ian Salt, Institute of Cardiovascular & Medical Sciences

Colin Selman, Institute of Biodiversity, Animal Health and Comparative Medicine

PhD project summary:

Over the past few decades it has become apparent that brown adipose tissue (BAT) is a possible target for disorders associated with obesity, as BAT increases energy expenditure through non-shivering thermogenesis. AMP-activated protein kinase (AMPK) is a key regulator of cellular and whole-body energy homeostasis, acting to sense energy depletion and stimulate ATP conservation and synthesis. AMPK activation has therefore also been proposed as a therapeutic target for cardiometabolic diseases. Despite significant understanding of the role of AMPK in the principal metabolic tissues (liver, muscle and, to a lesser extent, white adipose tissue), very little is understood concerning the role of AMPK in BAT metabolism. This project will test the hypothesis that AMPK activation influences nutrient uptake, storage and oxidation in brown adipocytes under conditions promoting storage of triglycerides and thermogenesis. The project will use several cell biology and biochemical techniques, including mammalian cell culture, nutrient uptake and metabolism assays using metabolic tracers and cell signaling analyses using techniques including immunofluorescence confocal microscopy, immunoblotting and flow cytometry.

Supervisors:

Colin Selman, Institute of Biodiversity, Animal Health & Comparative Medicine

Paul Shiels, Institute of Cancer Sciences

PhD project summary:

RNA polymerase III (Pol III) is one of three eukaryotic, nuclear RNA polymerases that generates short, non-coding RNA, including the transfer RNAs (tRNAs) and the 5S ribosomal RNA (rRNA). Pol III plays a pivotal role in protein synthesis and ribosomal biogenesis, and excitingly it has been shown that Pol III plays an evolutionary conserved role in organismal longevity; partial inhibition of Pol III extends lifespan in yeast, C. elegans and Drosophila. We are currently extending these studies to determine the role of Pol III in mammalian longevity. Protein synthesis accounts for a high proportion of the metabolic costs of an organism at rest. Given the central role of Pol III in protein synthesis, we predict that modulating Pol III is likely to have major implications to the metabolic phenotype of mice (e.g. mitochondrial function, ROS production, lipolysis), that is likely to be exacerbated during the ageing process and under conditions of nutrient excess. This project will combine whole-animal metabolic approaches, alongside mitochondrial functional analysis, and general molecular biology approaches to better understand the role of Pol III in nutritional excess. Given that many of the effects of over-nutrition on metabolism, health and longevity is sex-specific, we will study both male and female mice.   

Supervisors:
Dr Lilach Sheiner
Dr Andrew Maclean

PhD project summary:
Perkinsus marinus is a single-celled eukaryotic parasite of oysters causing losses of millions of dollars annually. It also belongs to a larger group of organisms (myzozoans)which include human pathogens such as the malaria-causing Plasmodium. The mitochondrial biology of myzozoans is highly divergent from that of humans and these differences can be exploited for therapeutic intervention. Despite this the mitochondrial biology of myzozoans is not well understood. This project aims to develop Perkinsus as a model organism to study myzozoan mitochondrial biology. New genetic tools for Perkinsus, and the fact it can cultured axenically, make a perfect and timely organism for structural and biochemical studies. During the PhD, initially the candidate will explore the composition of mitochondrial complexes using proteomics techniques to determine how divergent the complexes are from current models. From these, the candidate can select mitochondrial complexes they wish to focus on for further studies, using structural biology approaches to understand what the complex looks like and how it functions. Additionally, developing and using genetic manipulation tools, the candidate can probe the function of these complexes. Overall, this project will explore the fascinating divergent mitochondrial biology of Perkinsus parasites and provide training in cutting-edge cell biology and biochemistry techniques.

Supervisors:

Kimberly Fornace, Institute of Biodiversity, Animal Health & Comparative Medicine

Heather Ferguson, Institute of Biodiversity, Animal Health & Comparative Medicine

PhD Project Summary:

To address the growing climate emergency, an increasing number of initiatives are focused on reforestation and environmental restoration. However, the impacts of these programmes on disease transmission remain unknown. Reforestation projects may inadvertently create new vector breeding sites or impact behaviour and distribution of wildlife and people. This project will work closely with Regrow Borneo, a reforestation project based in Sabah, Malaysia, to assess the impact of reforestation on risks of zoonotic and vector-borne diseases, including zoonotic malaria and arboviruses. Detailed environmental data will be used to design spatially representative longitudinal entomological sampling, assessing the abundance and infection rates of mosquito vector species. Additionally, acoustic and imagery data to evaluate how land management practices impact the distribution of people and wildlife hosts during peak vector biting times. Data will be integrated into mathematical models to evaluate the impacts of reforestation projects on disease spillover and transmission. Final models will be used to explore impacts of future reforestation projects and identify targets for disease surveillance.

This project will be conducted in partnership with conservation organisations and wildlife and health departments. This will include extensive fieldwork based in Sabah, Malaysia in addition to training on quantitative analysis methods. The successful candidate will work closely with a multidisciplinary team based in the UK and Malaysia.  

Supervisors:

Simon Babayan, Institute of Biodiversity, Animal Health & Comparative Medicine

Georgia Perona-Wright, Institute of Infection, Immunity & Inflammation

PhD project summary:

Individuals vary substantially in their responses to immunisation, but the underlying causes of such variation and what to do about it are poorly understood. This has important consequences for our ability to bring new vaccines to the general public (only a small fraction make it past clinical trials) and for our ability to predict who to prioritise and what proportion of the population needs to be vaccinated. Under pandemic scenarios, these knowledge gaps are particularly concerning. We hypothesise (i) that this variability is primarily driven by differences in diet, past and current coinfection with viruses and worms, age and sex, and (ii) that under resource limitation (e.g., nutritional), individuals prioritise antiviral responses to only invest in anti-helminthic immunity if sufficient nutritional resources are available. This project aims to test predictions deriving from those eco-evolutionary hypotheses using immunisation experiments in laboratory and wild mouse populations in which diet and parasite infection are manipulated; immunological, demographic and parasitological data; as well as Bayesian and structural causal modelling. This is a multidisciplinary and collaborative project that has scope to adapt to the student’s interests and will include all basic training across disciplines where needed.

Supervisors:

Simon Milling, Institute of Infection, Immunity & Inflammation

Kevin Maloy, Institute of Infection, Immunity & Inflammation

PhD project summary:

Inflammatory bowel disease (IBD) is an incurable and debilitating chronic condition, increasingly common in the UK. Expensive targeted immunological drugs are now commonly used for IBD management. While these can be highly effective, each is typically only useful in about 30% of patients, and those who fail to respond are less likely to benefit from a secondary therapy. A better molecular understanding of the mechanisms that drive IBD in different individuals may help identify appropriate therapeutics.

We performed RNA sequencing using samples of inflamed intestinal tissue from patients with Crohn’s disease (CD), one of the two types of IBD. We identified individuals with different macrophage functions, including altered inflammasome responses. We have begun to explore these pathways by analysing localisation of key proteins expressed by these different macrophage types.

This project aims to understand cellular and molecular mechanisms that control macrophage functions, in order to develop more precise and effective treatments for CD. We hypothesise that the heterogenous responses in CD are controlled by these specific pathways, and that careful examination of intestinal T cell and macrophage responses, paired with clinical data, will enable identification of the contributions of these different pathways in CD patients.

Supervisors:

Heather Ferguson, Institute of Biodiversity, Animal Health & Comparative Medicine

Mafalda Viana, Institute of Biodiversity, Animal Health & Comparative Medicine

Luca Nelli, Institute of Biodiversity, Animal Health & Comparative Medicine

Nicodem Govella, Ifakara Health Institute (Affiliate Researcher, IBAHCM)

PhD Project Summary:

Pathogens spread by mosquito vectors are a major source of mortality and morbidity in human, livestock and wildlife populations.  Amongst these, malaria places the biggest burden on human health; particularly in Africa where >90% of cases occur. Insecticide Treated Nets (ITN) have been the most effective method of reducing malaria transmission, but the success of this approach is highly dependent on the interplay between human and mosquito behaviour.  ITNs work best where mosquitoes bite indoors during sleeping hours, and net usage is high.  Recent evidence suggests that both the human and mosquito behaviours that determine the protection gained from ITNs vary in response to microclimatic conditions. This project aims to assess the contribution of local microclimatic conditions to exposure to malaria vectors and use of ITNs across ecologically distinct settings in Tanzania. The studentship will be embedded within an ongoing collaboration between the Ifakara Health Institute (IHI) in Tanzania and the University of Glasgow that is investigating environmental determinants of malaria transmission and control impact. The project will draw heavily on analysis of existing data, with opportunity to visit collaborators at the IHI and observe field work. Results will inform understanding of how current and future climate conditions may impact vector control approaches.

Supervisors:

Anna Amtmann, Institute of Molecular, Cell and Systems Biology

Matt Jones, Institute of Molecular, Cell and Systems Biology

PhD project summary:

A big challenge for plants is how to manage the trade-off between CO₂ uptake and water loss under climate stress such as heat and drought. In this PhD project you will use infrared gas analysis (IRGA) systems to control temperature, humidity and light on individual plant leaves and measure gas exchange. Your research will build on recent discoveries indicating that experience of environmental change by one leaf leads to systemic responses in other leaves, and that the leaves respond differently depending on their position within the plant and the plant canopy. These findings highlight a sophisticated system of communication and task distribution between individual leaves that could be used to optimize crop yields in the field. The aim of this project is to explore the spatial and kinetic properties of the stress responses, to identify the molecular nature of the signals, and to unravel the signaling pathways related to hormones (ABA, JA), reactive oxygen species (ROS), Ca²⁺ and electric waves. You will acquire practical skills in cutting-edge methodologies for plant physiology, genetics and molecular biology.  You will work in a laboratory with state-of the-art equipment and facilities and you will receive training from scientists with outstanding international reputation.

Supervisors:

Rucha Karnik, Institute of Molecular, Cell and Systems Biology

Mike Blatt, Institute of Molecular, Cell and Systems Biology

Catherine Kidner, University of Edinburgh

PhD project summary:

Globally, agricultural fresh-water usage has increased 6-fold in the past 100 years, twice as fast as the human population, and is expected to double again before 2030, driven mainly by agriculture. In the UK, irrigation has risen 10-fold in the past 30 years and this trend is expected to continue. Stomata of plants are microscopic pores driving plant gas and water exchanges with the environment and they have a major influence on the water and carbon cycles of the world. Stomatal behaviours, including movement, density and patterning impacts photosynthetic rates by over 50% when demand exceeds water supply affecting plant productivity against water use. Plant water use efficiency (WUE), defined as the amount of dry matter produced per unit of water transpired is directly related to stomatal function. Engineering stomata for enhanced water use efficiencies is of highest interest towards enhanced crop performance. This project is to mine genetic information from Begonia that display unique stomatal clusters. The knowledge gained will be used to manipulate stomatal biogenesis and engineer stomatal patterning using Arabidopsis thaliana as a model. Using genetic, molecular, physiological and biochemical approaches structure function mechanisms affecting stomatal development will be solved. This work is pivotal for mitigating the imminent crisis for agricultural food and freshwater availability as a consequence of climate change.

Supervisors:

John Christie, Institute of Molecular, Cell and Systems Biology

Eirini Kaiserli, Institute of Molecular, Cell and Systems Biology

PhD Project Summary:

Global warming is a major threat for worldwide crop productivity. The only way to tackle this problem is to generate thermo-tolerant crops without compromising crop yield. Thus, understanding how plants respond and adapt to fluctuating temperatures is key for optimizing plant growth in response to a changing environment. However, light and temperature are interconnected environmental factors that regulate plant development and adaptation. Indeed, it is well established that the plant red/far-red light receptor phytochrome functions as a thermosensor through temperature effects on its thermal reversion to the ground state. Evidence is also emerging that other photoreceptors function as thermosensors in plants. More insight on how light and temperature signals crosstalk at the molecular level is needed to identify new targets for agricultural gain. Our labs (Christie and Kaiserli) have recently used a genetic overexpression approach to discover novel genes promoting thermo-tolerance in plants. We have screened an Arabidopsis library overexpressing over 10,000 genes (RIKEN FOX lines; Ichikawa et al., 2006) and identified a key protein that fine-tunes plant responses to high light and temperature regimes providing an excellent candidate for optimizing plant growth in response to light and temperature changes and a model for studying environmental signal adaptation at the molecular level.

Supervisors:

Harriet Auty, Institute of Biodiversity, Animal Health & Comparative Medicine

Louise Matthews, Institute of Biodiversity, Animal Health & Comparative Medicine

Mike Barrett, Institute of Infection, Immunity & Inflammation

PhD project summary:

Drug resistant infections are a global issue impacting human health, livestock health and the livelihoods of those dependent on livestock. African Animal Trypanosomiasis (AAT) is a major constraint on sub-Saharan African agriculture and food security with ~60 million cattle at risk and 3 million deaths/year.

Rising reports of treatment failures mean there is an urgent need for sustainable control strategies that enable farmers to reduce the burden of disease whilst limiting the development of drug resistance.  The availability of new drug treatments and rapid diagnostics mean this is the right time to develop control strategies that exploit new technologies and maintain the efficacy of new drug treatments.

Using extensive data from our study sites in Tanzania, the successful candidate will develop epidemiological models of the transmission and control of trypanosomiasis. These models will be used to determine the optimal deployment of drug treatments, insecticides alongside use of rapid diagnostics, as function of key variables including production system, local disease incidence, presence of wildlife and existing rates of drug resistance. These models will be used to practical develop guidelines for farmers that are tailored to their livestock system, thereby enabling local farmer-led disease control.

Supervisors:

Esther K. Papies, School of Psychology and Neuroscience

Emilie Combet, School of Medicine

PhD Project Summary:

Food systems are responsible for about 34% of global greenhouse gas emissions, especially from the production of red meat.  Meat consumption is also associated with significant health risks, including different forms of cancer and cardiovascular disease. Yet, eating meat is the norm across society, and UK dietary guidelines (Eatwell Guide) even recommend the consumption of red meat.  In this interdisciplinary project, we will examine the role of nutritional guidelines in the social norms around eating meat and its perceived health and environmental benefits and threats.  Then, we will assess the most effective way of changing dietary recommendations to facilitate nutritionally balanced meat reduction among mainstream consumers. The project supervisors are experts in the psychology of behaviour change and in nutrition and dietary guidelines. The student will receive expert training in among others, survey and experimental methods for psychology, dietary assessment, advanced statistical analyses in R, nutritional implications of meat intake, and the role of social norms in dietary change.

Supervisors:

Louise Matthews, Institute of Biodiversity, Animal Health & Comparative Medicine

Taya Forde, Institute of Biodiversity, Animal Health & Comparative Medicine

PhD project summary:

Multi-drug resistant bacteria present a growing, global crisis that threatens our healthcare systems. ESBL- producing Enterobacteriaceae (ESBL-PE) are a class of resistant bacteria that have been designated critical on the WHO’s list of priority pathogens. These resistant pathogens pose a major burden within hospital settings requiring treatment with expensive and last resort antibiotics. The situation is especially acute in lower- and middle-income countries where the burden of infection is high and resources to tackle antimicrobial resistance are limited. Reducing the impact of ESBL-PE requires a multi-pronged approach including reducing antibiotic usage, more rapid diagnostics, and improved infection-prevention-control (IPC) measures. The overall aim of this project is to quantify the major sources of infection and routes of transmission of ESBL-PE in hospital patients and to use these findings to identify the most effective interventions. The project will use whole genome sequence data from a large bank of isolates collected from hospitals, the community, and livestock in Northern Tanzania. The student will receive extensive training in molecular epidemiology and epidemiological modelling and use these tools to examine the sources and transmission routes of resistant bacteria within hospital patients, with a focus on neonatal care, and use these findings to examine potential interventions.

Supervisors:
Dr Mick Craig
Prof Jonathan Cavanagh
Prof Brian Morris

PhD project summary:
The claustrum is an enigmatic brain region that is connected with most other parts of the brain, and has been implicated in supporting cognitive flexibility, decision-making and possibly even consciousness. Sitting below the cortex, the claustrum has been difficult to study until the advent of modern genetic tools. In this project, we will use cutting-edge methods of studying and manipulating neural circuit function to determine whether changes to the function and connectivity of the claustrum underlie behavioural changes associated with schizophrenia.

Using mice that model heightened genetic risk of developing schizophrenia, this project will use a combination of patch-clamp electrophysiology and optogenetics, viral tracing and behaviour with chemogenetics to unravel the circuitry of the claustrum. By specifically targeting neurons that connect with prefrontal cortex and other regions important for cognition, we will determine whether altering activity of claustrum neurons is sufficient to rescue behavioural deficits in transgenic mice, or induce these deficits in wildtype mice.

Supervisors:
Prof Matthew Berriman
Prof James Cotton

PhD project summary:
Schistosomiasis is a major neglected tropical disease caused by blood flukes of the genus Schistosoma. Fundamental research into schistosomiasis is needed to inform the search for new approaches to disease intervention. Schistosoma mansoni is one of the clinically most important species, and the most widely studied. A high-quality genome reference has provided the foundation for large-scale studies of schistosome biology, with extensive data available on gene expression and function. Most of this work has been restricted to investigating protein-coding genes. Non-coding RNA (ncRNA) genes play diverse roles in regulating gene expression, but we have only a limited understanding of these loci in schistosomes. In this project, we will systematically identify ncRNA genes in S. mansoni and characterise their expression in different stages of the schistosome lifecycle and in different tissues. Understanding how well conserved these genes across schistosome species will help identify key loci for validation and functional investigation. Depending on the interests of the student, this could be a purely computational project or involve generating novel sequencing data for ncRNAs. The student would receive high-level training in bioinformatics and data science, including genome analysis and annotation, analysing and interpreting high-throughput sequencing and single-cell data. 

Supervisors:
Prof Kathryn Elmer
Prof Maureen Bain

PhD project summary:
Reproduction is key to the physiology, development, and life history of animals and the biological bases are deeply shared across amniotes. Viviparity has evolved more than 100 times in mammals and reptiles and its evolutionary novelty is how mothers modulate duration of pregnancy and reduction in offspring number. These are presumed to be genetic but are also affected by proximate and long-term environmental context. To date, experiments to deconstruct environmental from intrinsic and extrinsic genetic components of female reproductive investment were not possible and therefore the molecular basis of pregnancy duration and its evolution is not known.

In this project we will identify genetic determinants of reproductive investment and pregnancy duration, including partitioning the influence of maternal vs paternal effects. This is uniquely possible using an emerging model organism for amniote live-bearing – the common lizard, Zootoca vivipara. We will quantify the variation in gestation time using a combination of developmental biology and genetic approaches. Further, we will use genome-wide pedigrees to determine the contribution of paternal genetic variation on i) maternal reproductive strategies and ii) offspring investment and outcome. The experiments will involve new field collections, microscopy and developmental biology, and genomic analyses for high resolution parentage reconstruction. Demonstrating the genetics of reproductive timing and investment is key to identifying how major changes in reproductive mode occur, resolving genetic and evolutionary conflicts between sexes and generations, and improving knowledge of influences to pregnancy outcomes.

Supervisors:
Lisa Ranford-Cartwright
Virginia Howick

PhD project summary:
There are over 220 million cases of human malaria caused by Plasmodium falciparum per year, and around 400,000 people die of severe forms of the disease. Identifying and targeting better health care to those individuals most at risk of severe disease and death is a priority to reduce mortality rates, but at present there is no clear marker, either in the host or parasite, associated with increased risk of mortality. Higher parasite growth rates in the blood, leading to increased parasite burdens, are associated with higher morbidity and mortality. The aim of this project is to identify the gene(s) in the human malaria parasite P. falciparum that determine differential rates of intraerythrocytic growth. The approach to achieve this aim will be to analyses growth rates in progeny clones from a genetic cross between two P. falciparum clones, and then to identify regions of the genomes associated with different growth rates using quantitative trait locus (qtl) analysis. Finally, the role of genes identified in this screen will be confirmed by genetically modifying the parasites using crispr/cas9 technology to “swap” the alleles present, and then investigate the growth rates of the modified parasites.

Supervisors:
Prof John Riddell
Dr Mick Craig

PhD project summary:
Chronic pain has a high prevalence (30 – 50% of the UK population) and is often poorly controlled by current analgesic treatments. There is therefore a major unmet clinical need for improved pain therapies and an understanding of the mechanism underlying the development of pain states is necessary for the rational development of novel analgesics. However, multiple potential mechanisms are implicated in the development and maintenance of chronic pain states of different causes and our knowledge of these remains incomplete. There is evidence that reciprocal connections between the primary somatosensory and anterior cingulate cortices are important for pain processing and there is also some indication that these connections are altered in chronic pain states. These so-called plastic changes in the function of brain circuits likely underly altered perception such as allodynia, where normally non-painful stimuli become painful. In this project, we will investigate cortical pain circuits in rodents using viral tract-tracing in vivo and whole cell recording approaches in brain slices, combined with optogenetics. We will identify the neuronal subtypes contributing to these reciprocal connections and then use chemogentic manipulations targeting these connections to investigate their role in acute pain processing and in the development of pain states in animal models of neuropathic pain.

Supervisors:
Dr Stephen Carter
Dr Edward Hutchinson

PhD project summary:
If we could simply look at a virus inside a eukaryotic cell and observe all the host and virus molecules interacting with one another in their native state, we would vastly improve our understanding of the virus life cycle and the cellular innate immune responses. To understand virus-host interactions using cryo-ET technology we are proposing to address an important biological question targeting the M1 protein of influenza A virus (IAV). Influenza viruses are representative of many emerging viruses which pose a high-risk to human and animal health. This proposal is designed to answer important questions about the structural, mechanistic, and biological details of M1 assemblies inside the nucleus and their association with RNPs during export from the nucleus (Terrier et al., 2012).

To do this, our research will apply state of the art in situ structural biology technologies, such as cryo-CLEM, cryo-FIB milling, cryo-ET, and STA to visualize IAV M1 assemblies at high-resolution. Using these techniques, we will look for novel structural aspects of the pro-viral processes that take place during the influenza infection inside the nucleus. With this approach we aim elucidate a wealth of structural insights into the global architecture of M1 assemblies, with the possibility of revealing novel interactions with nucleosomes and host-cell complexes. By looking at these complexes using sub-tomogram averaging (STA) approaches our aim is to see whether M1 tubes interact with chromosomes, and if they do how the nucleosome architecture is changed in the presence of M1 tube formation, and whether there is cellular specificity in how M1 filaments are built.

Supervisors:
Prof Kostas Tokatlidis
Dr Alberto Sanz

PhD project summary:
Maintenance of functional mitochondria is essential for life and an important therapeutic target in several diseases. Mitochondria biogenesis and function relies on accurate protein import mechanisms to the organelle. On the other hand, misfolding of mitochondrial proteins and aggregation poses a threat to cell homeostasis. We have discovered that maintaining the redox state in mitochondria requires alternative targeting to mitochondria via completely unknownmechanisms, whilst redox-regulated release of misfolded proteins into the cytosol is critical for clearance of this burden from mitochondria. In this project we will study the novel mechanisms of (i) stress-induced targeting to mitochondria and (ii) redox-regulated unfolded protein response as a mitochondria-localised quality control mechanism. We will use an interdisciplinary approach combining genetic, biochemical, cell biology, chemical and structural biology approaches together with omics technologies to develop new knowledge. The mitochondrial proteostasis and fitness mechanisms that will be studied in this project have important ramifications in the maintenance of a healthy protein balance in the cell and the cell’s response to stress, particularly in age-related diseases.

Supervisors:
Prof Andrew Todd
Dr David Hughes

PhD project summary:
Pain and itch are major clinical problems that cause great personal suffering. It is estimated that chronic pain affects ~20% of the population, and that 1 in 3 patients are unresponsive to currently available treatments. Our failure to offer effective relief for a significant proportion of the population presents serious welfare problems and serves to highlight how little is known about the cellular basis of sensory systems in health and disease. In this project we will investigate the role played by a discrete population of spinal interneurons in influencing our perception of itch and pain. These inhibitory interneurons (iCRs) are defined by the expression of the protein calretinin and we aim to target them selectively by using viral vectors injected into transgenic mice. These cutting-edge approaches will help us define the synaptic connectivity of these cells in spinal circuits, and understand the influence that they have on pain and itch perception under normal and pathological conditions. This project will provide important insights into the organisation of spinal circuits responsible for processing sensory information, and importantly, will reveal whether iCRs represent a target for new treatments that could be used to alleviate chronic pain and itch.

Supervisors:
Prof Marios Philiastides
Prof Lars Muckli

PhD project summary:
Decision making is one of the most ubiquitous tasks in our everyday life. Recent developments in cognitive neuroscience have established that decision-making involves a process of temporal integration of information – supporting different choice alternatives – until an internal decision boundary has been reached. This accumulation-to-bound mechanism, however, requires a separate process for controlling the tradeoff between the urgency of committing to a decision and other task demands, such as the amount of available evidence and the likely gains (or losses) involved in making a particular decision. For example, imagine having to make a difficult investment decision which requires integrating several pieces of information to ensure a favourable outcome, but you are working against a tight deadline. How do you balance the urgency to submit a bid before the deadline while at the same time evaluate the evidence as accurately as possible to maximise your chances for success? While recent studies have identified brain nodes involved in the process of evidence accumulation itself, relatively little has been done to identify and characterize the network interactions controlling the tradeoff between different task demands as highlighted in the example above. We have recently advocated for a new theoretical framework, which addresses this open question. In this project we will aim to offer neurobiological validation of this framework by leveraging computational modelling and a first-of-its-kind brain imaging platform (fusion of human EEG with high resolution (7T) fMRI data) to identify the relevant brain networks and their interactions.