- James Anderson, M.D., Ph.D. Research
Epithelial cells make up critical barriers that separate outside and inside, whether within the skin or in internal organs and tissues. The Anderson lab has long been interested in the primary mechanism that binds these cells together to create these barriers: the tight junction. His group studies how these transmembrane complexes regulate the movement of material between neighboring epithelial and endothelial cells, ranging from small electrolytes to larger travelers like immune cells looking for pathogens.
Using kidney epithelia as a model system, Dr. Anderson’s lab has been among the leaders in identifying the many individual proteins that make up the tight junction structure. His team was the first to propose and demonstrate that the transmembrane claudin proteins create charge-selective pores in the tight junction and that different members of the claudin family confer different ion selectivity. Together, Dr. Anderson’s claudin research has provided significant insight toward our current knowledge regarding the molecular basis of selective paracellular transport and inherited human defects of the junction barrier. His group has also demonstrated that the protein Zonula Occludens-1 stabilizes the tight junction barrier by linking the tight junction to the actin cytoskeleton.
While continuing to characterize some of the key players in the tight junction, Dr. Anderson’s group is progressing towards higher order studies of the tight junction complex. Hundreds of tight junction-associated proteins have been identified to date, and the next step is to understand the organizational structure. Through crosslinking studies, proximity labeling methods and a variety of imaging approaches, his group is examining protein interactions to identify multi-protein assemblies within the tight junction. Additional studies using biotinylation and mass spectrometry are helping divide these several hundred tight junction proteins into discrete functional groups, such as being directly involved in maintaining the barrier, establishing cell polarity, or regulating endocytic trafficking, to name just a few. Currently real-time super-resolution microscopy approaches and biophysical methods are being used to reveal the dynamic interaction among tight junction proteins and their coupling to the cytoskeleton.
Ultimately, this additional insight into tight junction organization and regulation may lead to approaches enabling manipulation of the barrier permeability, which opens up numerous applications. For example, tight junctions are frequently disrupted and “leaky” during inflammation, resulting in improper movement of fluid and cells and characteristic symptoms such as tissue swelling; therapeutic manipulation with drugs might quickly restore barrier integrity. Conversely, subtle loosening of the tight junction in some locales, notably the blood-brain barrier, may allow for improved delivery of antibiotics or other drugs to the brain.