Supervisors

Lead Supervisor:

Dr Jonathan Witton, University of Exeter, Department of Clinical and Biomedical Sciences

Co-Supervisor:

Dr Valentina Mosienko, University of Bristol, Department of School of Physiology, Pharmacology & Neuroscience

Professor Jonathan Brown, University of Exeter, Department of Department of Clinical and Biomedical Sciences

Professor Wendy Noble, University of Exeter, Department of Clinical and Biomedical Sciences

The GW4 BioMed2 MRC DTP is offering up to 21 funded studentships across a range of biomedical disciplines, with a start date of October 2025.

These four-year studentships provide funding for fees and stipend at the rate set by the UK Research Councils, as well as other research training and support costs, and are available to UK and International students.

About the GW4 BioMed2 Doctoral Training Partnership

The partnership brings together the Universities of Bath, Bristol, Cardiff (lead) and Exeter to develop the next generation of biomedical researchers. Students will have access to the combined research strengths, training expertise and resources of the four research-intensive universities, with opportunities to participate in interdisciplinary and 'team science'. The DTP already has over 90 studentships over 6 cohorts in its first phase, along with 58 students over 3 cohorts in its second phase.

The 120 projects available for application, are aligned to the following themes;

• Infection, Immunity, Antimicrobial Resistance and Repair

• Neuroscience and Mental Health

• Population Health Sciences

 

Applications open on 10th September 2024 and close at 5.00pm on 4th November 2024.

Studentships will be 4 years full time.  Part time study is also available.

Project Information

Research Theme:

Neuroscience & Mental Health

Summary:

Microglia are brain-resident immune cells. Alongside conventional molecular signals, the latest research suggests that specific patterns of brain activity can control microglia function. We have found that a type of brain activity normally activated during cognition (called gamma oscillations) signals to microglia via a receptor subgroup, which may drive a neuroprotective response. Using a novel experimental assay developed by our lab, this project will uncover how this signalling works to reveal new drug targets for treating conditions where immune systems in the brain malfunction, such as in Alzheimer’s disease.

Main Description: 

Microglia are brain-resident immune cells that provide the main form of defence against neuropathology. It is well known that there is dynamic crosstalk between microglia and neuronal cells that maintains brain homeostasis and coordinates neuroimmune responses. Recent studies, however, have identified a new form of neuron-microglia communication driven by rhythmic neuronal activity.

Communication between neurons generates rhythmic patterns of electrical brain activity, called neuronal oscillations. Studies have revealed that neuronal oscillations around 40 Hz – called gamma oscillations – generate a signal that regulates microglia function (PMID: 31076275). Specifically, gamma oscillations induce a homeostatic and neuroprotective immune response linked to enhanced microglia surveillance and phagocytosis that can clear pathological proteins (like amyloid-β) in mouse models of Alzheimer’s disease (AD) (PMID: 27929004).

This is important because impaired gamma oscillations and abnormal microglia function are cardinal features of neurodegenerative diseases like AD, thereby raising the tantalising possibility that these diseases could be treated by triggering Gamma-Activity Induced Neuron-microglia Signalling (hereinafter, GAINS).

However, very little is known about how GAINS works due to a lack of tractable models of this phenomenon. To this end, we have developed a new model of GAINS in ex vivo mouse brain slices and have used it to discover that GAINS occurs via colony stimulating factor 1 receptors (CSF1R), which are expressed by microglia, and via nuclear factor kappa B (NFκB) pathway signalling (manuscript in prep.). Excitingly, molecular targets of CSF1Rs and NFκB overlap with signalling pathways linked to AD risk genes (PMID: 24951455, PMID: 29312321) and targets of AD medicines in clinical trial (e.g. NCT05744401).

QUESTION & AIMS

The scientific question at the heart of this project is "What are the specific cellular and molecular mechanisms underlying GAINS?" Building on our current data, we hypothesise that GAINS is mediated by factors downstream of microglial CSF1Rs that converge on NFκB pathway activation. Objectives to test this hypothesis are:

(1) Identify molecular mediators of GAINS downstream of CSF1R signalling ex vivo.

(2) Validate molecular mediators of GAINS in vivo.

(3) Explore the role of astrocytes as a cellular source of GAINS-evoked CSF1.

PROJECT DESIGN

Objective 1 will be tackled using ex vivo models of GAINS developed in our lab. Gamma oscillations will be induced in mouse brain slices using pharmacology and optogenetic techniques and recorded using electrophysiology, whilst changes in the properties of fluorescence tagged microglia (labelled using Alexa 488 isolectin B4) are measured using 2-photon microscopy (e.g. morphology, density, motility). Several molecular pathways link CSF1Rs to NFκB, including MAP kinase-ERK, protein kinase C, and PI3 kinase-Akt; (PMID: 35290551). We will test the role these pathways play in GAINS using commercially available inhibitors of molecules involved in each signalling pathway.

Objective 2, we will test whether GAINS is regulated by CSF1Rs and their downstream molecular targets in vivo. We will induce gamma oscillations in mice using optogenetics (mirroring our slice model) and via 40 Hz light stimulation that can drive GAINS in visual cortex (PMID: 3106275). Mice will be treated with antagonists for CSF1Rs (e.g. BLZ945) or inhibitors of their targets that block GAINS ex vivo (i.e. in Objective 1). We will also use acute in vivo 2-photon brain imaging in mice to measure microglia dynamics (e.g. motility, migration) during GAINS and when it is pharmacologically blocked. Astrocytes are cells that provide a key source of CSF1 in the brain (PMID: 34472465).

Objective 3 will leverage our ex vivo assay to test the role of astrocytes in GAINS. Specifically, we will disrupt astrocyte function during GAINS in brain slices by inhibiting astrocyte metabolism using drugs (e.g. aminoadipic acid) or viral-genetic tools developed by co supervisor Mosienko.

STUDENT OWNERSHIP Our project objectives are not mutually exclusive, and thus different research lines can run in parallel and be tailored to the student’s interests. As the project incorporates both ex vivo (Objectives 1 & 3) and in vivo (Objective 2) models, the student can balance the focus of the project between these different types of experiment depending on their interests and prior experience. Similarly, the student can balance the focus between cellular/molecular signalling (Objectives 1 & 2) and astrocyte focussed (Objective 3) experiments in line with their interests.

Additionally, whilst not an explicit focus of the project, co-supervisors Mosienko and Noble have significant molecular biology expertise to facilitate analysis of GAINS-driven changes in microglia and astrocyte gene and/or protein expression; this direction could also be facilitated by our team’s active collaborations with Exeter’s Complex Disease Epigenomics Group (https://www.epigenomicslab.com/) if this is of interest to the student.

OUTCOMES The project will discover cellular and molecular mechanisms underlying a novel neuroimmune pathway that could be leveraged to treat neurodegenerative disorders characterised by aberrant gamma oscillations and disrupted neuroimmune function, like AD.

Funding

This studentship is funded through GW4BioMed2 MRC Doctoral Training Partnership. It consists of UK tuition fees, as well as a Doctoral Stipend matching UK Research Council National Minimum (£19,237 p.a. for 2024/25, updated each year).

Additional research training and support funding of up to £5,000 per annum is also available.

Eligibility

Residency:

The GW4 BioMed2 MRC DTP studentships are available to UK and International applicants. Following Brexit, the UKRI now classifies EU students as international unless they have rights under the EU Settlement Scheme. The GW4 partners have agreed to cover the difference in costs between home and international tuition fees. This means that international candidates will not be expected to cover this cost and will be fully funded but need to be aware that they will be required to cover the cost of their student visa, healthcare surcharge and other costs of moving to the UK to do a PhD.  All studentships will be competitively awarded and there is a limit to the number of International students that we can accept into our programme (up to 30% cap across our partners per annum).

Academic criteria:

Applicants for a studentship must have obtained, or be about to obtain, a first or upper second-class UK honours degree, or the equivalent qualification gained outside the UK, in an appropriate area of medical sciences, computing, mathematics or the physical sciences.  Applicants with a lower second class will only be considered if they also have a Master’s degree. Please check the entry requirements of the home institution for each project of interest before completing an application. Academic qualifications are considered alongside significant relevant non-academic experience.

English requirements:

If English is not your first language you will need to meet the English language requirements of the university that will host your PhD by the start of the programme. Please refer to the details in the following web page for further information https://www.exeter.ac.uk/study/englishlanguagerequirements/

Data Protection

If you are applying for a place on a collaborative programme of doctoral training provided by Cardiff University and other universities, research organisations and/or partners please be aware that your personal data will be used and disclosed for the purposes set out below.

Your personal data will always be processed in accordance with the General Data Protection Regulations of 2018. Cardiff University (“University”) will remain a data controller for the personal data it holds, and other universities, research organisations and/or partners (“HEIs”) may also become data controllers for the relevant personal data they receive as a result of their participation in the collaborative programme of doctoral training (“Programme”).

Further Information

For an overview of the MRC GW4 BioMed programme please see the website www.gw4biomed.ac.uk

Entry requirements

Academic Requirements

Applicants for a studentship must have obtained, or be about to obtain, a first or upper second-class UK honours degree, or the equivalent qualification gained outside the UK, in an appropriate area of medical sciences, computing, mathematics or the physical sciences. Applicants with a lower second class will only be considered if they also have a Master’s degree. Please check the entry requirements of the home institution for each project of interest before completing an application. Academic qualifications are considered alongside significant relevant non-academic experience.

English Language Requirements

If English is not your first language you will need to meet the English language requirements of the university that will host your PhD by the start of the programme. Please refer to the relevant university website for further information.  This will be at least 6.5 in IELTS or an acceptable equivalent.  Please refer to the English Language requirements web page for further information.

How to apply

A list of all the projects and how to apply is available on the DTP’s website at gw4biomed.ac.uk.  You may apply for up to 2 projects and submit one application per candidate only.

Please complete an application to the GW4 BioMed2 MRC DTP for an ‘offer of funding’.  If successful, you will also need to make an application for an 'offer to study' to your chosen institution.

Please complete the online application form linked from our website by 5.00pm on Monday, 4th November 2024.  If you are shortlisted for interview, you will be notified from Friday, 20th December 2024.  Interviews will be held virtually on 23rd and 24th January 2025.

Further Information

For informal enquiries, please contact GW4BioMed@cardiff.ac.uk

For project related queries, please contact the respective supervisors listed on the project descriptions on our website.

Summary