University of Bristol PGR scholarships in Health Sciences

Details

Our ability to remember ‘where I put my car keys today’ as opposed to ‘where I put them yesterday’ depends on a computational process known as pattern separation. Pattern separation refers to the representation of highly similar memories in distinct ways so they can coexist without interference; and one of the first memory processes affected by ageing.

Pattern separation is a function of the hippocampal DG that comprises granule cells, mossy cells, and different types of interneurons. Mossy cells, in particular, are essential to pattern separation and key regulators of the balance between excitation and inhibition in DG circuitry.

In preliminary work, we have found that pattern separation memory deficits are linearly correlated with DG volume loss in the MRI scans of young epilepsy patients, and that the post-mortem brains of young epilepsy patients have fewer DG mossy cells, a pathological finding that is more typical of older adults.

Mossy cell death is known to be caused by seizure activity but may also lead to further disinhibition and hyperexcitability of the hippocampal DG in epilepsy patients. Hence, mossy cell death may be implicated in both the pathogenesis of recurrent seizures and the memory deficits that affect many patients with epilepsy.

Aims and objectives

Hypothesis: Epilepsy patients have pattern separation deficits because of the death of mossy cells from seizures.

Aim 1: To measure pattern separation in epilepsy patients using the mnemonic similarity task, a well-established behavioural test of pattern separation memory

Aim 2: To correlate the results of aim 1 with measurements of (a) DG volume from MRI scans, and (b) histopathological mossy cell density from surgical specimens (only patients who have temporal lobe epilepsy surgery)

Aim 3: To model the dynamics of pattern separation in the DG and use this to understand how seizures and mossy cell loss and lead to deficits

Methodology

50% of patients with drug-resistant epilepsy assessed by the Bristol epilepsy surgery services (>100 adults and >50 children annually) are eligible for surgery. Their standard assessment includes:

• EEG/video-telemetry
• 3T MRI head scans
• Neuropsychology work-up

In this research project (IRAS 229579 approved on 15 July 2022), the student will:

• recruit adults and children with temporal lobe (TLE) or generalised epilepsy (50 in each group)
• direct subjects to complete the online 10-15min Mnemonic Similarity Task (MST)
• ask subjects about their quality of life, epilepsy, and anti-epilepsy medications using online questionnaires in REDCap.
• histologically quantify different cell populations in the DG for those TLE patients who have surgery and ask these subjects to repeat the online MST and questionnaires when 3, 6 and 12 months have elapsed since their surgery (to determine how MST performance changes with seizure frequency in the post-operative period).
• correlate the results of the questionnaires, MST +/-histology with the MRI/EEG/neuropsychology results collected from subjects as part of their standard care.
• Develop a neural mass model of DG circuitry to model patient EEG data. The model will be used to predict the effect of mossy cell death and pharmacological agents, e.g., anti-epileptics, on pattern separation and epilepsy.

Apply for this project

This project will be based in Bristol Medical School - Translational Health Sciences.

Please apply using the Online Application System. You should search for the "Translational Health Sciences (PhD)" programme with a start date of September 2023, then click the "Apply" button.

IMPORTANT: In the Funding section under "Main source of funding" please select "University of Bristol Scholarship"

We strongly recommend that you list at least two alternative projects in your covering letter, as we may not be able to offer you your first choice. Please only submit one application (to your first choice school/department), but note that your other choices can be based in another school/department.

Apply now!

Details

Genome wide association studies enable the mapping of genetic effects to molecular phenotypes (such as gene expression levels or protein levels in specific tissues), and those genetic effects can then be mapped to disease traits for causal inference using a statistical framework known as Mendelian randomisation (e.g. Zheng et al 2021). However, recent work has demonstrated that the complexity of genetic relationships at the molecular phenotype layer far exceeds that which can be permitted by the assumptions used in previous causal modelling approaches (e.g. Min et al 2021). There are several issues that may be contributing to difficulties of causal modelling. First, our genetic effects on molecular phenotypes lack specificity because of e.g 1) genetic relationships being developed in readily available tissue samples which fail to separate differences in genetic effects between cell types within the tissue; or 2) the genetic effects are shared by different omic layers. Second, the standard approach to causal inference which treats a few molecules at a time in discrete time fails to capture the coordinated ‘state-based’ regulatory landscape within the cell.

Aims and objectives

1. Develop cell-type specific genetic effect estimates on molecules by using emerging cellular deconvolution methods, especially in large scale datasets such as DNA methylation assays in the Million Veterans Program
2. Generate an accurate genotype-phenotype map amongst molecular phenotypes within a single genomic region.
3. Use heterogeneity of genetic effects across cell types and molecular phenotypes in a region to improve causal inference of the regional landscape on complex disease endpoints
4. Evaluate through simulation whether the observed patterns of regional genotype-phenotype maps are consistent with state-based regulatory causal models

Methodology

This project will bring together large scale molecular and genetic datasets with an exploration of statistical methodology and simulation of biological models. The candidate will receive strong support from the supervisory team, which will also include researchers at Harvard who coordinate the Million Veterans Program.

Data sources:

• DNA methylation and protein measures on 50k samples in the Million Veterans Programme
• Protein levels on 50k samples in the UK Biobank
• Gene expression levels from GTEx and eQTLGen
• Genetic effects on disease endpoints from OpenGWAS (Elsworth et al 2020)
• MRC multi-ancestry cohort network

We will adapt methods such as SuSIE (Zoe et al 2021), PAINTOR (Kichaev et al 2017), hyprcoloc (Foley et al 2021), cellular deconvolution (Donovan et al 2020) and LD correction measures (Chen et al 2021) for construction of regional genotype-phenotype maps.

Simulations will be conducted using approaches such as those in the simulateGP package (https://github.com/explodecomputer/simulateGP/) as well us using dynamic single cell models (Pratapa et al 2020).

Causal models will build upon multivariable MR approaches (Sanderson et al 2018, Sadler et al 2021), and we will investigate the integration of structural priors and competing model selection approaches.

Apply for this project

This project will be based in Bristol Medical School - Population Health Sciences.

Please apply using the Online Application System. You should search for the "Population Health Sciences (PhD)" programme with a start date of September 2023, then click the "Apply" button.

IMPORTANT: In the Funding section under "Main source of funding" please select "University of Bristol Scholarship"

We strongly recommend that you list at least two alternative projects in your covering letter, as we may not be able to offer you your first choice. Please only submit one application (to your first choice school/department), but note that your other choices can be based in another school/department.

Apply now!

Details

Prostate cancer is the UK’s commonest male cancer and represents a significant public health challenge. The UK National Screening Committee currently does not recommend prostate cancer screening1. The CAP randomised controlled trial (RCT) was influential in this recommendation, showing no significant prostate cancer-specific mortality benefit of one-time PSA screening at 10-years follow-up [rate ratio 0.96 (95%CI:0.85,1.08)].2 There are also concerns about screening’s adverse-effects on men’s quality-of-life through biopsy-related complications, overdiagnosis and overtreatment.

Utilising the long-term follow-up data from CAP provides the opportunity to consider whether any diagnostic factors affect the long-term outcomes for an individual man. This studentship could provide information that would help doctors decide diagnostic tests and treatments for prostate cancer, that would maximise the benefits and potentially reduce the harms from screening. Questions such as, what PSA cut point should be selected to start the screening programme? Answers to these questions could be used to build prognostic tools.3

Aims and objectives

Determine if measurements at diagnosis (age, PSA level and tumour characteristics) help doctors predict long-term outcomes for an individual man, to better decide his diagnostic tests and treatments for prostate cancer. Enabling the provision of high-quality information to help men and their doctors understand the possible benefits and harms of prostate cancer screening and will potentially be used by the National Screening Committee to update their prostate cancer-screening recommendations for the NHS.

1. Determine the performance of screening (age, PSA) and diagnostic (Gleason, stage) variables to predict 15-year PCa-mortality to inform diagnostic and treatment strategies.

Methodology

CAP randomised 415,357 men aged 50-69 from 573 primary-care practices across 8 centres in England and Wales between 2001-2009. This work exploits the continued linkage of >96% of the originally randomised CAP trial men to routine electronic NHS databases, making data collection and analysis extremely efficient. This PhD studentship offers the opportunity to develop working relationships with the experienced CAP RCT research team of clinical and non-clinical researchers.

Whilst working with linked data, and potentially conducting supplementary data collection of granular prostate cancer Gleason grade, provides the opportunity for students to develop data science and statistical skills.

Beginning with a review of existing prostate cancer screening literature, and through discussion with clinical advisors the student will develop clinically meaningful comparisons for inclusion in the model to determine the performance of screening and diagnostic variables.

The student will fit a Cox regression model to evaluate the individual and joint performance of routine screening (age, PSA) and diagnosis (Gleason, T stage) variables in predicting 15-year prostate cancer-specific mortality. Testing assumptions (e.g., proportional hazards) and examine alternative methods (e.g., time-specific mortality rate-ratios4). Predictive performance will be evaluated using discrimination, calibration, decision-curve analysis and comparison with existing models.

Apply for this project

This project will be based in Bristol Medical School - Population Health Sciences.

Please apply using the Online Application System. You should search for the "Population Health Sciences (PhD)" programme with a start date of September 2023, then click the "Apply" button.

IMPORTANT: In the Funding section under "Main source of funding" please select "University of Bristol Scholarship"

We strongly recommend that you list at least two alternative projects in your covering letter, as we may not be able to offer you your first choice. Please only submit one application (to your first choice school/department), but note that your other choices can be based in another school/department.

Apply now!

Details

White matter impairments are a major component of various neurodegenerative diseases, including Alzheimer’s disease(1,2). White matter is composed of neuronal axons and their encasing myelin; a lipid-rich material produced by the oligodendroglia. Myelin insulates axons to sustain optimal action potential conduction, and therefore its loss causes neuronal transmission impairment. Accordingly, remyelination could represent an effective therapeutic target. Indeed, a recent report found that promoting myelin renewal in an in vivo model of Alzheimer’s disease improved cognitive function(3). However, we currently lack an effective way to promote remyelination in the brain.

Ultrasound has been used extensively as a diagnostic imaging tool in medicine for over 60 years. Surprisingly, studies in humans and animal models have revealed that when ultrasound is directed across the skull, it can profoundly modulate brain activity(4–6). We have shown that ultrasound exposure enhances neuronal function(7). Importantly, oligodendrocytes express various mechanosensors, whose activation drives proliferation and differentiation of oligodendrocyte precursor cells and myelination8. This presents the intriguing possibility that extraneously applied movement forces – such as those induced by ultrasound – could be used to drive an active state of oligodendrocytes and ultimately promote myelination.

Aims and objectives

Aim 1: Determine ultrasound effects on oligodendrocytes.

Objectives: 1. Characterise ultrasound parameters and how they relate with effects on oligodendrocytes. 2. Examine consequences of ultrasound on remyelination.

Hypothesis: Ultrasound stimulates the proliferation, migration and differentiation of oligodendroglial progenitor cells and promotes remyelination of demyelinated axons.

Aim 2: Determine how targeted transcranial ultrasound affects neurodegenerative pathology in an Alzheimer’s disease mouse model.

Objectives: 1. Test disease-modifying effects of ultrasound. 2. Characterise effects of ultrasound on remyelination. 3. Examine how ultrasound affects cognition.

Hypothesis: Transcranial ultrasound exposure induces remyelination in a rodent Alzheimer’s disease model, with beneficial effects on cellular and cognition.

Methodology

We will prepare rat organotypic hippocampal slice cultures, and test how ultrasound exposure affects the extent of remyelination in a chemically induced model of demyelination. This will be assessed through immunocytochemistry and high-resolution imaging using established markers of oligodendroglial lineage in the CNS. The consequences of this on neuronal function will be explored through electrophysiology. In complementary studies informed by the in vitro work, we will test the effects of ultrasound exposure in vivo in an established and previously validated transgenic mouse model of Alzheimer’s disease and the consequences for behaviour and cognition. The student will therefore develop a range of highly sought-after technical skills, including electrophysiology, protein analysis, high-resolution cell imaging, in vivo expertise, and animal behaviour analysis.

Apply for this project

This project will be based in Bristol Medical School - Translational Health Sciences.

Please apply using the Online Application System. You should search for the "Translational Health Sciences (PhD)" programme with a start date of September 2023, then click the "Apply" button.

IMPORTANT: In the Funding section under "Main source of funding" please select "University of Bristol Scholarship"

We strongly recommend that you list at least two alternative projects in your covering letter, as we may not be able to offer you your first choice. Please only submit one application (to your first choice school/department), but note that your other choices can be based in another school/department.

Apply now!

Details

In recent years there has been increased concern around the prescribing of medications associated with dependence and withdrawal. These medications include opioids, benzodiazepines and gabapentinoids[1,2]. One particular concern is polypharmacy, because annual statistics show combinations are implicated in rising numbers of deaths[3,4]. Implicated opioids may be pharmaceuticals for pain, opioid substitution therapy (OST) e.g., methadone or illicit drugs like heroin. Although caution is advised on co-prescribing benzodiazepines and gabapentinoids alongside opioids, including to people who misuse opioids, anecdotally this is known to occur. This project will determine the scale of co-prescribing of these medications, including to those with a known history of opioid misuse. Contributing factors will be explored in depth, to help inform opioid stewardship (OS) interventions for use in general practice. OS is coordinated interventions designed to improve, monitor, and evaluate the use of opioids, to protect and improve health.

Aims and objectives

This study has two aims and five objectives. To fit with word limit, the aims only are included:

Aim 1. To determine levels of co-prescribing of opioids, benzodiazepines and gabapentinoids in adults in the UK and to determine the extent and variation in adverse outcomes for these medications, including in people with a history of opioid misuse.

Aim 2: To understand co-prescribing of opioids, benzodiazepines and gabapentinoids in depth and identify targets to modify prescribing behaviour to build into an OS intervention.

Hypothesis: co-prescribing patterns present increased risk of overdose.

Methodology

1. Scoping Literature Review of opioid stewardship practice and outcomes in general practice. (review skills)
2. Observational retrospective study using data from the Clinical Practice Research Datalink (CPRD) Aurum data to form a cohort of adults newly prescribed opioids, benzodiazepines or gabapentinoids. This group will be matched to a healthy comparator group who do not receive these medications. The full cohort will be followed over time from the point of their first prescription until they die, stop contributing data to the study or until the end of the study period (2010-2022). Patient outcomes will be identified along with the use of healthcare, co-prescribing and comorbidities that may have an impact on outcomes. Analyses will take into account the type of medication prescribed, changes in prescription and prescribing patterns, dose, and any combinations of therapy as well as the length of time these are prescribed for. (Big data skills)
3. Qualitative interview study with prescribers in general practice, to give greater depth to understanding the findings from (2). Analysis will take a reflexive thematic approach, informed by behaviour change theory (COM-B/TDF), to understand prescriber practice and to identify modifiable targets to build into a future opioid stewardship intervention. (Qualitative skills)

Apply for this project

This project will be based in Bristol Medical School - Population Health Sciences.

Please apply using the Online Application System. You should search for the "Population Health Sciences (PhD)" programme with a start date of September 2023, then click the "Apply" button.

IMPORTANT: In the Funding section under "Main source of funding" please select "University of Bristol Scholarship"

We strongly recommend that you list at least two alternative projects in your covering letter, as we may not be able to offer you your first choice. Please only submit one application (to your first choice school/department), but note that your other choices can be based in another school/department.

Apply now!