Investigating the influence of antioxidant signalling on blood brain barrier integrity
Applicants with passion in defeating dementia are invited to apply for an exciting PhD project on preventing blood brain barrier dysfunction to combat neurodegenerative disease at the world-leading UK Dementia Research Institute at the University of Edinburgh.
Project designed around your scientific vision with direction from your supervisors
Multidisciplinary topic at the heart of the Edinburgh UK DRI’s mission
Supervision from UK DRI ‘s Rowling Fellow Jing Qiu, Centre Director Hardingham, and BHF Fellow Andre Caporali
State-of-the-art labs and facilities at the UK Dementia Research Institute
Supportive and vibrant Edinburgh Neuroscience training environment
Full Stipend/salary, UK or international tuition fees, consumables and travel
The blood brain barrier (BBB) is at the interface of the brain parenchyma and the cerebrovasculature that supplies the brain with essential nutrients. Its function is to control the transport of molecules and to provide a strong barricade against infiltration of circulating solutes or immune cells into the brain. It is made up of brain endothelial cells, a surrounding basement membrane containing pericytes, plus astrocytes. Neuroinflammation can occur when BBB function is compromised, which can happen acutely following systemic infection, or chronically in cerebral small vessel disease (cSVD) and Alzheimer’s disease. There is therefore a need for therapeutic strategies which preserve BBB integrity and prevent the production of pro-inflammatory factors. Evidence suggests that antioxidants can help to preserve endothelial barrier function but are difficult to administer in sufficient doses, and only have specificity for particular types of reactive oxygen species. To circumvent this, we have performed a screen of drugs for their ability to increase cells’ own intrinsic antioxidant defences, testing all compounds that have passed Phase 1 clinical trials (i.e. are safe). Positive hits include activators of Nrf2, a master regulator of endogenous antioxidant defences, as well as molecules of unknown mechanism.
Rationale & Hypothesis:
We have developed an in vitro model of the BBB, which enables the study of trans-BBB transport, BBB-secreted proteins, and real-time monitoring of barrier integrity. We hypothesize that pharmacological manipulation of endothelial antioxidant defences with compounds from our screen will help to preserve BBB integrity and inhibit inflammatory signaling, some via Nrf2 activation and others by novel mechanisms.
- Assemble the in vitro human BBB system to measure endothelial barrier function and to characterize the BBB secretome in the face of infection, and define those secreted factors important for neuroinflammation
- Manipulate Nrf2 activity by pharmacological activation, or siRNA-mediated knockdown, to determine the effect on the BBB secretome and barrier function, as well as on downstream microglial activation, in response to peripheral inflammation.
- Investigate the influence of the newly identified antioxidant-inducing drugs, and perform genome-wide transcriptome analysis plus follow-up investigations to probe their mechanism of action.
- Generate a human BBB system incorporating endothelial cells with mutation that causes cSVD in humans, profile the deficits observed and assess rescue strategies defined in Aims 1 and 2.
Outputs: this project will uncover the mechanisms behind inflammatory signaling across the BBB in an all-human cellular system. Moreover it will identify barrier-preserving drugs and their mechanism of action, all of which are safe for use in humans.
Supervisory and collaboration team:
This project will be supervised by Dr Jing Qiu, an expert in glial signalling , co-supervised by Dr Andrea Caporali, an expert in vascular biology and Prof Giles Hardingham, an expert in neurodegeneration, also in collaboration with Prof Siddharthan Chandran, an expert in stem cell technology and Director of the Anne Rowling Regenerative Neurology Clinic, and Prof David Hunt, an expert in neuroinflammation.
Supervisors’ latest publications:
Jiwaji Z, Tiwari SS, Avilés-Reyes RX, Hooley M, Hampton D, Torvell M, Johnson DA, McQueen J, Qiu J, Spires-Jones TL, Johnson JA, Chandran S, Hardingham GE. (2022). Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology. Nat Commun. 2022 Jan 10;13(1):135. doi: 10.1038/s41467-021-27702-w. PMID: 35013236.
Baxter, P., Dando, O., He, X., Hardingham, GE, and Qiu, J. (2021). Neurons and astrocytes combine to maintain microglia maturity and regulate inflammatory responses in vitro. Cell Reports 34. (*corresponding author).
Qiu, J., Dando, O., Febery, J.A., Fowler, J.H., Chandran, S., and Hardingham, G.E. (2020). Neuronal Activity and Its Role in Controlling Antioxidant Genes. Int J Mol Sci 21.
The closing date for the application is 5.00 pm GMT, Monday 28th February 2022. Interviews will take place in March with project beginning in October 2022.
Applications are open to candidates worldwide; there are no restrictions on nationality/residency. The successful applicant, once accepted, will register on the Neuroscience (Biomedical Sciences – Centre for Discovery Brain Sciences) PhD programme, and all applicants should ensure that they meet the eligibility requirements for this programme. International applicants should pay particular attention to the requirements specific to their country. Do not apply directly to the programme now.
Suitable MSc and/or BSc (at least 2:1 or equivalent) in a relevant subject (including, but not necessarily limited to, neuroscience biomedical sciences, biochemistry, molecular biology, and genetics). Applicants should have research experience in a relevant discipline.
The studentship will be funded by the Anne Rowling Regenerative Neurology Clinic, a University of Edinburgh research facility that delivers care and research to improve the lives of people with degenerative conditions affecting the brain. The studentship includes three years of stipend payments at the standard UKRI rate, UK /full international tuition fees and funds for conference attendance and training, as well as all associated research costs. As part of the Anne Rowling Clinic the student will have the opportunity to meet people living with neurodegenerative conditions and take part in patient and public involvement and engagement events.
For more information, please contact Dr Jing Qiu (firstname.lastname@example.org).