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Reverse engineering a human blood-brain barrier platform for studying neurovascular diseases

   Department of Materials

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  Prof N Hooper, Dr Marco Domingos  No more applications being accepted  Funded PhD Project (Students Worldwide)

About the Project

To apply for this programme, please visit Informal enquiries are welcome, to [Email Address Removed].

ABM CDT Dysregulation of the blood-brain barrier (BBB) is an early and critical event in the pathogenesis of neurovascular diseases, such as Alzheimer’s disease, vascular dementia and stroke. However, there is a lack of knowledge of the molecular and cellular mechanisms underlying the breakdown of the BBB in these diseases due to the difficulty in studying the BBB in vivo. The multicellular neurovascular unit (NVU) is central to the regulation of BBB function in health and its dysfunction in neurovascular diseases. The NVU comprises endothelial cells, pericytes, astrocytes and neurons. Complex and dynamic interactions between these cells and the surrounding extracellular matrix (ECM) regulate BBB (dys)function. Appropriate BBB models are essential for understanding the pathological neurovascular functions in Alzheimer’s and vascular dementia and for studying the transport efficacy of drugs that target the brain. Highly robust, predictive and cost-effective in vitro BBB models are needed that accurately recapitulate the complex cell-cell and cell-ECM interactions within the NVU. This project will focus on incorporating hydrogels that mimic the physical and chemical properties of the brain ECM, 3D bioprinting and microfluidic technology to recapitulate the capillary blood flow, along with the co-culture of human induced pluripotent stem cell (iPSC)-derived endothelial cells, pericytes, neurons and astrocytes, to reverse engineer a 3D BBB model. This reverse engineered BBB model will exhibit physiologically relevant structures such as tight junctions and its permeability will be comparable to in vivo values, providing a platform to study neurovascular (dys)function and to screen for brain-targeting drugs.

Main questions to be answered:

Components of the ECM, such as heparan sulphate proteoglycans (HSPGs), promote the formation and aggregation of amyloid which drives the development of Alzheimer’s disease. In ageing the expression of alkaline phosphatase increases, leading to altered metabolism of collagen in the ECM, calcification and, through unknown mechanisms, decreases in BBB transport. This project will use iPSC-derived endothelial cells, astrocytes, pericytes and neurons, in conjunction with novel hydrogels, 3D bioprinting and microfluidic technology to reverse engineer a human BBB model which will be used to answer these questions:

  1. what is the most appropriate natural hydrogel that recapitulates the in vivo mechanical (stiffness, elasticity and viscosity) and biochemical (cell adhesion) properties and supports the growth of the multiple NVU cell types?
  2. what is the effect of alteration of the ECM (e.g. increased stiffness, reduction in proteoglycan content) on BBB function and amyloid deposition?
  3. will alteration of alkaline phosphatase activity lead to alterations in BBB integrity and amyloid deposition, and,
  4. what are the molecular mechanisms underlying this?

In addition, the optimised reverse engineered BBB platform will be used to screen for soluble ligands and small molecules that may have the ability to rescue the BBB dysfunction in Alzheimer’s disease.

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