Tight junction proteins seal the space between adjacent epithelial and endothelial cells and form paracellular pores that regulate the paracellular transport: pore-forming claudins. Unfortunately, biophysics of these pore-forming claudins remains incompletely undefined. Mutations in pore-forming claudins cause human disease, including familial hypomagnesemia and hypercalcuria, neonatal sclerosing cholangitis associated with ichthyosis, and others. Underlying structure-function relationships will fundamentally advance our understanding of paracellular permeability and may, ultimately, lead to novel therapeutic approaches. The Dynchan project aims to develop a new technology that will enable high resolution analyses of claudin channel activity and regulation. The technology based on silicon chips with array of nanopillar electrodes is expected to provide the tool needed to develop foundational understanding of claudin biology.
The unprecedented integration of high aspect ratio structures into the lateral intercellular space sets the stage for application of nanotechnologies for perturbation and analysis of epithelial tight junction biology. This nanoelectrode arrays will enable other basic and applied studies and ultimately support development of therapeutics designed to modulate claudin function. The recent breakthrough discovery that tight junction channels might be actively-gated (i.e., transitioning between open and closed states) has identified a new plausible avenue to treat barrier-related diseases. Development of the Dynchan technology will accelerate advances in understanding of paracellular channel gating, without which the biophysics of the pore-forming claudin functions will remain incompletely undefined.
This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 896293. (https://cordis.europa.eu/project/id/896293).