New PhD opportunity funded by Race Against Dementia. Closes Friday 12 December.

Race Against Dementia: All Hands Team Vascular

Vascular causes of dementia are common. Cerebral small vessel disease (cSVD) is the leading cause of vascular cognitive impairment (VCI) and vascular dementia (VaD) including in mixed dementias with Alzheimer’s disease. Despite causing up to 45% of dementias, research and established treatments for vascular causes of dementia are lacking. Race Against Dementia (RAD): Team Vascular - Prevention and Treatment of Vascular Cognitive Impairment and Dementia is a cross-disciplinary team working together to prevent and treat vascular causes of cognitive impairment and dementia, with expertise in cSVD, Alzheimer’s disease and dementia, clinical research including trials, discovery science, and data science including experimental validity, literature and drug data interrogation. The Team comprises four interconnected workstreams: LACI-Cog, a pilot trial in patients with cognitive decline; LACI-Rat, conducting randomised trials in preclinical rodent models; LACI-Hunt, to develop efficient methods of searching for new drug targets and drugs; and LACI-Ignite, to advocate for the importance of vascular causes of dementia, foster awareness, and promote interest amongst early career and senior researchers, funders and policy-makers.

Background:

We created and characterized the Atp11b-knockout (KO) transgenic rat which shows pathological imaging and behavioural characteristics similar to those found in human cerebral small vessel disease (SVD) in spite of being normotensive. This rat first shows endothelial cell dysfunction followed by white matter changes in the brain, with cognitive and mobility decline. We have shown that these detrimental changes can be ameliorated using a variety of different drugs with actions on endothelial cells.

As part of LACI-rat, the student will use this rat model both to test other potential drugs of benefit, with readouts of pathology and behaviour, as well as seeking to understand how these drugs are having their effect – on endothelial cells and other brain cells. The student will work closely with the LACI-Hunt team who are using systemic literature searches and machine learning paradigms to identify potential drugs to test.

Aims:

1. To test the multiple drugs identified through LACI-Hunt that may benefit SVD in vitro on dysfunctional (Atp11bKO endothelial cells) to determine if they reverse endothelial cell dysfunction. This will provide information about the mechanism of action of these drugs as well as providing a prioritisation step for moving into in vivo studies.
2. To test selected drugs identified through LACI-Hunt for their action on other relevant Atp11bKO brain cells (e.g. oligodendrocytes, microglia) to identify those with beneficial effects e.g. increasing oligodendrocyte myelin production, reducing disease-associated microglial signatures as appropriate for the drug class. Again, this will provide information about the mechanism of action of these drugs, potential added benefit/side effects and further providing a prioritisation step for moving into in vivo studies.
3. To test the prioritised drugs in vivo in an established Rat trial protocol (LACI-Rat) to determine whether they can prevent (at early time-points) or reverse (at later time-points) SVD-like pathology, as well as deterioriation in mobility and cognition

Supervisors and Environment

All supervisors are experienced researchers, bring complementary skills to tackle vascular causes of cognitive decline and dementia, and world leading in their respective topics. They are all trained in PhD regulations, Equality & Diversity and Unconscious Bias, student mentoring and training, and are approved by the UoE to be a supervisor.

• Prof Anna Williams - Professor of Regenerative Neurology
• Prof Malcolm Macleod - Professor of Neurology and Translational Neuroscience
• Prof Joanna Wardlaw - Professor of Applied Neuroimaging
• Centre for Regenerative Medicine, Institute for Regeneration and Repair
• Institute for Neuroscience and Cardiovascular Medicine
• Row Fogo Centre

Further information, including how to apply can be accessed from the following links: 

Testing and understanding potential drugs of benefit to cerebral small vessel disease in a rat model at University of Edinburgh on FindAPhD.com

PhD opportunities | Centre for Regenerative Medicine