Organ-on-chip models to study the effect of genetic variants on microvascular barriers in neurological disorders

• Applicant: Dr. Annette Lischka
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 542345724

The blood-brain-barrier (BBB) and the blood-nerve-barrier (BNB) form a protective barrier around the nerves in the central and peripheral nervous systems. Given the importance of these structures in maintaining nerve homeostasis, loss of BBB and BNB function have been causally associated with neurological disease. To date, the BBB has been the primary focus of research efforts, given its role in the central nervous system, while the BNB has been explored to a significantly lesser extent, especially in terms of genetic variation. This biased exploratory approach of the nervous system has hampered the understanding of those pathologies attributed to the peripheral nervous system, such as hereditary pain disorders. To address this unmet need, we propose the use of human-derived brain microvascular endothelial cells (BMVECs), pericytes, neurons, and astrocytes grown in organ-on-chip and transwell systems to recapitulate the BBB and BNB. Transwell and organ-on-chip approaches mimic the BBB and BNB architecture and are amenable to high-throughput and NGS approaches. Initially, the influence of different genetic variants on transendothelial electrical resistance (TEER) and permeability of the BBB will be determined. Subsequently, single cell RNAseq will be used to analyze the gene expression pattern of the various cell populations within the BBB organ-on-a-chip environment. Similar techniques and strategies will then be applied to determine the influence of genetic variants associated with inherited pain disorders on BNB integrity, permeability, and gene expression. This will yield significant insight into the mechanisms by which BNB dysfunction influences inherited pain disorders, which is a clinically relevant and underexplored research area.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Hosts: Dr. James Gorman; Professor Dr. Rakesh Karmacharya