Tight Junctions

 

A group of biochemists at the University of Nebraska-Lincoln earned a five-year, $1.8 million grant to understand the structure, function and dysfunction of tight junctions.

Alex Vecchio, assistant professor in biochemistry, said in an email that the $1.8 million grant, the Maximizing Investigators’ Research Award, is to fund the researchers’ studies about how the structure and assembly of membrane proteins influence the function of human tight junctions.

Sewwandi Rathnayake, postdoctoral research associate at the Vecchio Lab, said in an email that tight junctions are multi-protein complexes assembled across cell membranes of neighboring epithelial and endothelial cells, which will act as barriers preventing the entry of harmful substances into the cells. 

Endothelial cells form a single cell layer which lines all blood vessels, and signals from these cells organize the growth and development of connective tissue cells. Epithelial cells work as a barrier between the inside and outside of the human body and protects the body from viruses.

“Basically, they help cells to pack ‘tightly’ next to each other,” Rathnayake said. “Tight junctions occur throughout the human body, covering surfaces to lining various body cavities and glands.”

Rathnayake said studying about tight junctions is important since dysfunctional tight junctions lead to the development of diseases like food poisoning, loss of hearing, neurological disorders and cancer. 

“Our research will also be very valuable in helping fellow researchers in the field to design therapies for diseases that arise due to tight junction dysfunction,” Rathnayake said.

Rathnayake said the grant will pay for research equipment and personnel. Rathnayake said the researchers will use biophysical, biochemical and molecular biology techniques to address their research questions.

Vecchio said the aim of the research is to formulate new ideas and understanding on how these membrane proteins assemble and function by determining their individual and associated three-dimensional structures. The three-dimensional structures of these proteins can be determined at the atomic level using structural biology methods, according to Vecchio.

Once the protein structures are visualized, the researchers can use their knowledge of biochemistry and biophysics to infer how the protein functions at the molecular level, according to Vecchio. These inferences can then be tested at the cellular or tissue levels to better understand how the proteins influence the function and structure of tight junctions.

Tight junctions assemble at the top of epithelial cells and are composed of different proteins, according to Vecchio. As tight junctions sit just below the surfaces of epithelial tissues, they help individual cells adhere and also form a barrier to prevent molecules from moving in between these cells, according to Vecchio.

“Tight junctions are therefore the gatekeepers to passage of molecules in between cells,” Vecchio said. “The regulation of molecules in between cells is vital for the health and maintenance of epithelial tissues, which include skin, glands, organs and limbs.”

Vecchio said this research is important because there is little that is understood about how tight junctions assemble, disassemble and reassemble under normal or diseased conditions. The ultimate goal of the project is to begin to shed light on the structural bases of these phenomena, according to Vecchio.

“By understanding how these proteins fit together as pieces within a larger assembled puzzle, we can formulate new ideas for what goes wrong when some of the pieces are not shaped correctly and how the rest of the puzzle can or cannot form when those pieces are misshaped or missing,” Vecchio said.

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