Investigating and treating blood brain barrier dysfunction in vascular dementia

Applications are invited for a BHF 4-year MRes/PhD studentship starting in October 2022 at the National Heart and Lung Institute (NHLI) in partnership with the Bioengineering Department at Imperial College.

Students will join a well established doctoral training program with bespoke teaching activities, seminars, mentors and workshops.

The Cardiovascular Sections of the National Heart and Lung Institute, Imperial College, are located within the Main Campus at South Kensington, the Brompton Campus and Hammersmith/White City Campus. Bioengineering is also located at Main Campus at South Kensington and at White City. Students will have the opportunity to work in state of the art facilities within a highly developed research environment where our ambition is to translate research findings to help those with cardiovascular diseases. All students benefit from a full programme of training in research and transferable skills organised through the Graduate School, the quality of which has been recognised several times at the Times Higher Education (THE) Awards.

Project summary

The BHF 4-year MRes/PhD studentships typically comprises a 1-year MRes in Biomedical Research, followed by a 3-year PhD. During the MRes year, students undertake two laboratory projects which will prepare them for the PhD.

Supervisors: Professor Carling (https://lms.mrc.ac.uk/research-group/cellular-stress/) and Dr Scott (https://lms.mrc.ac.uk/research-group/genomics-of-obesity/) are both located at the MRC London Institute of Medical Sciences on the Hammersmith Hospital Campus. Professor Carling works on the role of AMP-activated protein kinase (AMPK) in the regulation of metabolism. His group use a combination of biochemical and physiological approaches to study the impact of altering AMPK activity on metabolism in disease e.g. obesity and type 2 diabetes. Dr Scott’s research focuses on human genetic and genomic studies to investigate metabolic disease mechanisms, and blood brain barrier function in dementia pathology. Both supervisors have strong collaborations with biomedical researchers in the Department of Brian Sciences and in Vascular Sciences at Imperial College.

Project Outline

Vascular dementia affects >10 million people worldwide. Outside of conventional risk factor modification there are no effective prevention or treatment strategies for vascular dementia. New therapeutics derived from increased understanding of disease mechanisms are a global health priority, and a key strategic goal of the BHF.

The blood brain barrier (BBB) is a highly selective semipermeable barrier made up of endothelial cells, pericytes and astrocytes that protects neurons from molecules and toxins circulating in blood. BBB breakdown is a major risk factor for vascular and other dementias that develops before disease onset. BBB dysfunction leads to neurocognitive dysfunction through two mechanisms: i. increased leakage of circulating toxins and pathogens into the brain which causes neuronal inflammation and damage; and ii. reduced clearance of brain-derived waste products which also causes neuronal injury. Reversing BBB dysfunction and subsequent neuronal damage is a promising strategy for preventing and treating vascular and other dementias.

The cellular and molecular mechanisms underlying BBB dysfunction remain poorly characterised. This knowledge gap is a major limitation to the development of new therapeutics for vascular and other dementias. Our preliminary studies in mouse models of human vascular dementia implicate BBB endothelial dysfunction in BBB leakage. We also find that therapeutic interventions targeted at improving endothelial function reverse BBB leakage in vascular dementia models.

This BHF PhD project will build upon our exciting preliminary findings with the aims of: (i) characterising in detail the cellular and molecular mechanisms underlying BBB damage, neuroinflammation and neuronal injury in vascular dementia; and (ii) evaluating different therapeutic interventions for reversing BBB endothelial mitochondrial dysfunction, BBB leakage and neurocognitive impairment.

Applicant Requirements

Applicants must hold, or expect to obtain, a first or upper second-class honours degree or equivalent in an appropriate subject from a recognised academic institution. Candidates must fulfil College admissions criteria and meet BHF residency requirements.

Applicants should be interested in developing interdisciplinary research skills in the following specific areas: molecular and cellular biology, in vivo physiology, neuro-imaging, therapeutics and data science.

How to Apply

To apply, please email Jaya Rajamanie ([Email Address Removed]) with the following documents.

• Your CV
• The names and addresses of at least two academic referees.
• A personal statement of no more than 1,000 words explaining your interest in the project and please ensure that you specify your degree classification for your undergraduate and postgraduate degrees.

Selected candidates will get a tour of the relevant campus. Please assume that your application has not been successful if you have not heard from us within a month of the closing date.

Closing date for all applications: 20^th February 2022

Interviews will be held online at the end of March.