Website [2] The University of Edinburgh
Closing Date: 12th May
PhD on how infection alters brain connectivity and immune signalling in vascular dementia using neuroimaging, in vivo models and computational analysis.
Title: Impact of infection on brain connectivity and contributions to vascular dementia
Synopsis: How infection modifies risk of vascular dementia is unclear. This interdisciplinary project will blend computational neuroimaging and cellular neuroimmunology approaches to investigate how infection influences changes to brain connectivity and cognitive function driven by chronic cerebrovascular disease. Immune-brain signalling mechanisms, including the role of microglia, will be examined and/or manipulated.
Background and rationale: Dementia is the leading cause of death in the UK and by 2040 it is projected that 1.4 million people will be living with dementia– understanding disease mechanisms and risk factors for cognitive decline are imperative to develop new treatments. Growing evidence suggests infections outside the brain (e.g. bacterial pneumonia) increase the risk of cognitive decline and dementia. This may involve immune-to-brain signalling that can alter the function of neural circuits and cells, including resident brain immune cells.
Infection increases the risk of all forms of dementia, yet the impact is greatest on vascular dementia (VaD) suggesting interplay between systemic immunity, brain vascular pathology and neuroinflammatory pathways. Our recent work in a preclinical VaD model supports this. In a parallel line of work using a neuroimaging approach in the same model, we have also shown that early alterations in brain connectivity can be used to predict outcome. Indeed, damage to the white matter of the brain, which forms its complex wiring and connectivity between regions, is a commonly consequence of cerebrovascular disease and important in VaD.
The proposed project aims to bring together interdisciplinary research into infection and immune brain signalling and computational neuroimaging approaches to better understand the impact of systemic infection on functional brain connectivity, underlying white matter health, and cognitive outcomes. We aim to establish neuroimmune pathways that represent causal mechanisms that explain the risk of dementia with infection and guide new treatments.
Objectives: The overall aim is to determine if infection (e.g. bacterial pneumonia) modifies the impact of chronic cerebrovascular disease on functional brain connectivity, neuroimmune activity and cognitive impairment
Specific objectives are to determine:
- The impact of infection on functional brain connectivity and cognition during chronic cerebrovascular disease
- How infection affects body-to-brain immune signals and brain immune cell profiles during chronic cerebrovascular disease
- The effects of depleting microglia/macrophages or discrete regulators on connectivity and cognition
Methodology: The project will use an exciting and innovative set of technical and analytical approaches blending the expertise of the project supervisors in neuroimmunology, modelling infectious complications in brain disease, and preclinical advanced neuroimaging. A mouse model of vascular cognitive impairment will be used to drive cerebrovascular and white matter pathology and combined with a model of lung infection. Functional ultrasound and/or MRI coupled with computational analyses will measure brain connectivity. Alongside, neuropathology, high-resolution microscopy and cellular immunoprofiling will be conducted. There will be opportunities to use bioinformatics approaches to data analysis.
Potential impact: The project may reveal targets both in body-to-brain immune communication and neuroinflammatory mechanisms to mitigate the impact of common infections on cognitive impairment. These could boost systemic immunity, dampen harmful inflammatory activity or enhance cognitive resilience. Information can be readily shared to clinical colleagues running clinical trials programmes in VaD.
Training: This interdisciplinary PhD will provide a comprehensive range of technical, analytical, and transferable skills training.
Our labs and facilities are located on the Edinburgh Bioquarter campus, a hub for life sciences research and innovation, health data and bioinformatics, and healthcare delivery. Leading research centres for clinical brain sciences, cardiovascular science, immunology/inflammation, and tissue repair are located alongside us on campus.
Opportunities for broader training in addition to gaining project-specific skills are extensive. The student will be part of a large postgraduate community with access to studentship-tailored transferable skills programmes, mentoring schemes and support for general academic development.
Project-related training:
- Preclinical neuroimaging: functional ultrasound and/or MRI acquisition and analysis; image processing pipelines (segmentation, registration and programming skills with Unix, Python and Matlab).
- Neuropathology: microscopy for cellular/structural measures
- Cellular immunoprofiling of brain and periphery (e.g., microglia/macrophage phenotyping)
- In vivo models: vascular cognitive impairment/white matter disease and bacterial pneumonia; manipulation of neuroimmune pathways
- Analytical: data processing and visualisation, statistical methods, experimental design
Professional and transferable skills:
- Communication: scientific writing, oral communication (e.g. lab meetings, conference presentations), public engagement, and opportunities to apply for early career grants
- Development of project planning and management skills, leadership, teamworking, mentoring opportunities (e.g., supervising UG/MSc students
Upon completion of this PhD, the student will have acquired a holistic set of skills that can offer potential to develop in several directions – we anticipate the PhD student will be highly competitive for careers in academia, biotech/pharma, imaging and analytics, and translational research.
Recruitment: We are looking for a motivated individual who has a strong interest in understanding infectious/immune contributions to brain function and dementia. An academic background featuring knowledge and experience in one or more of neuroscience, immunology, vascular biology, or neuroimaging would be beneficial. While training will be provided, any experience in using preclinical in vivo models of disease will be helpful.
Apply: All applications must be submitted through the Future Medicine PhD fellowships website [3].
Funding Notes
Students will receive a stipend at UKRI levels, plus £30K in travel and research funds across all three years of the fellowship. All University fees will be covered.
The fellowships are open to students who are eligible for home fees at Edinburgh – i.e. you must be a UK national, or have settled status, and have. been “ordinarily resident” in the UK for the three years immediately before the start of the fellowship. Other international applicants are not eligible for these fellowships.
To apply for this job please visit www.findaphd.com [4].