Leak and Pore Pathways

Paracellular permeability plays an important role in the pathogenesis of multiple disease states (see, e.g., Choi et al., Exp Cell Res. 2017 Sep 1;358(1):71-77. doi: 10.1016/j.yexcr.2017.03.036; Krug et al. Semin Cell Dev Biol. 2014 Dec;36:166-76. doi: 10.1016/j.semcdb.2014.09.002). Molecules move through the tight junction via two mechanisms. Small ions and small molecules cross the tight junction via a series of pores created by a family of proteins called claudins, the Pore Pathway (see figure). Macromolecules are too large to pass through these claudin pores. The claudin pores are both charge- and size-selective with a radius of 5-6 Angstroms. Some pore-forming claudins form pores that are cation-selective. A different subset of claudins form pores that are anion-selective. The cell- and tissue-specific expression of these different claudins underlies the different paracellular ion permeabilities of cells and tissues observed in vivo.

Macromolecules also cross the epithelium via the paracellular pathway, albeit at a much slower rate. They cross the tight junction through another pathway, the Leak Pathway. While the molecular properties of the Pore Pathway are being progressively unraveled, the molecular properties of the Leak Pathway remain unclear (see Amsler Lab Research - Leak Pathway Properties ). Our laboratory is investigating the molecular properties of the Leak Pathway and how the Leak Pathway is regulated under normal conditions and in disease states. In addition, we are seeking to understand how to regulate this pathway in a controlled manner, which may provide a mechanism for the delivery of therapeutic macromolecular drugs such as monoclonal antibody drugs, to patients.