PhD project but may also be considered for Honours project
The blood-brain barrier (BBB) lines the walls of brain microvessels, and is critical in preventing the entry of toxic molecules into the brain and enhancing the uptake of nutrients. The BBB is formed by brain endothelial cells (BECs), pericytes and neural cells (neurons and astrocytes) with BEC-expressed tight junction proteins (TJPs) and efflux transporters passively and actively, respectively, inhibiting the entry of toxic molecules into the brain. The BBB is critical in protecting brain health, but it simultaneously challenges the delivery of drugs into the brain for the treatment of central nervous system disorders. In addition, neurodegenerative diseases, including Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS), are associated with an impaired BBB structure, highlighting the contribution of the BBB on disease pathophysiology. However, the majority of our understanding of BBB structure and function is reliant on rodent models and given important species differences, establishing a reliable in vitro model of the human BBB is critical to increase our understanding of the human BBB in health and disease and aid in drug delivery. As a promising approach, several protocols have been published in recent years for the generation of BECs (iBECs) from human induced pluripotent stem cells (hiPSCs). This allows for the scalable generation of BBB cells and the study of disease-specific differences.
Objective: In this project, we will generate iBECs from patient-derived iPSCs to study differences in the BBB in neurodegenerative disorders compared to healthy controls. We will analyse differences in marker expression as well as functionality in iBECs to gain understanding into disease-specific effects. We will also analyse iBEC monolayer permeability using different compounds in single- and co-culture systems with other BBB cells to model drug delivery and to understand differences in the complete BBB system in a diseased brain compared to a healthy one. This project will be generate highly important information on how the human BBB is altered in neurodegenerative diseases and how this might affect therapeutic drug delivery. Findings from this project will contribute to a better understanding of human neurodegenerative disorders and help in the development of new BBB-permeable therapeutics to aid in the treatment of brain diseases.