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The Humane Research Trust is funding a research project at the University of Oxford into a common cause of stroke. The researchers will combine patient-derived cells and ‘organ-on-a-chip’ technology to model brain blood vessels. As a result, they will gain new insights into the factors underlying cerebral small vessel disease, a leading cause of stroke.
Cerebral small vessel disease (cSVD) is a major cause of age-related cognitive impairment, contributing to over 50% of dementia cases. It also accounts for more than 25% of ischemic strokes and the majority of intracerebral haemorrhages. This disease involves the malfunction of brain blood vessels, which can cause blockages and bleeds, severely damaging the brain. Despite its impact on patients, there are currently no effective treatments for cSVD.
The complexity in form and function of the brain vascular network meant previous research relied largely on animal models. However, human cells have been shown to display a number of key species-specific differences. As a result, there are difficulties translating results from animal models into clinical benefits for human patients. There is a clear need for new human models that better encapsulate the features of cSVD.
The Humane Research Trust is funding a new project at the University of Oxford into cSVD. The Trust awarded principal investigator Dr Paul Holloway with The David Millson Award. This grant was presented in honour of the late Dr David Millson, the Trust's former Chair of the Board.
The scientists aim to replicate the complex environment of brain blood vessels. They will do so using induced pluripotent stem cells derived from patients with hereditary forms of cSVD. They will grow the cells in a microfluidic ‘organ-on- chip’ system, cell culture ‘chips’ with miniature architectures at the scale of cells. In doing so, they will mimic the three-dimensional structure of brain blood vessels. This will help them study the cell interactions and learn how these are disrupted in cSVD.
Additionally, the researchers will explore potential treatments by targeting the extracellular matrix (ECM). The ECM is a network of proteins and other molecules that provide structural support to cells. In cSVD, the ECM can become degraded, contributing to disease progression. The researchers will test whether inhibiting certain enzymes that break down the ECM can help protect or repair the blood vessels.
“Due to the complexity of the human brain, studying the causes of disease and testing new drugs can be extremely difficult,” says Dr Holloway. “This work will provide a new alternative to animal models to enable the study of 3D vessels within a brain-relevant microenvironment.”
Dr Holloway and his team will focus on two types of cSVD: COL4A1 disease and CARASIL. They will characterise these models over 2 years, looking at various disease-relevant indicators. The approach will offer human-relevant insights into the cellular mechanisms behind the disease. Additionally, it will provide a human-based platform for drug testing and disease research. Potentially, this could transform how we study and treat conditions like stroke and dementia.
Dr Paul Holloway
Principal investigator
Dr Paul Holloway is a researcher in the Medical Sciences Division at the University of Oxford. His laboratory is focused on recreating and studying the cellular microenvironment within the brain-blood vessel system. This work combines with microfluidic technology with in vitro cell culture to develop physiologically relevant models of stroke.
Natalie King
Postdoctoral researcher
Natalie is a Postdoctoral Researcher who recently completed her PhD at the Perivascular Research Group, University of Tasmania. Here, she researched how issues with blood vessels contribute to diseases like Multiple Sclerosis, Alzheimer’s disease, and stroke.
