Epithelial Tight Junctions: Modulators of Tissue Adhesion, Transport, and Homeostasis
The explosion of diversity and increased complexity of animals over time, some argue, can be explained merely by the emergence and evolution of epithelium, a tissue where “form follows function”. My research aims to advance knowledge of this metazoan primary building block by characterizing in vivo and in vitro biochemical and biophysical properties of vital membrane proteins that modulate epithelial function. Specifically, my group studies tight junctions, membrane-bound multiprotein complexes involved in epithelial cell-cell adhesion, paracellular transport, and tissue homeostasis, with connections to diseases such as deafness, hepatitis, food poisoning, renal wasting, Alzheimer’s, MS, stroke, and cancer. Using techniques across interdisciplinary fields like molecular biology, cellular biotechnology, biochemistry, and structural biology – we thoroughly investigate tight junction protein structure–function relationships, discovering new paradigms for tissue integrity and insights into the molecular mechanisms underlying epithelial utility.
Epithelia function as a physical “barrier”, chemical “pore”, and also as a “fence" for differential transport of solutes and ions that regulate body fluid composition. Variations in animal organs, limbs, and glands result from epithelia developing features unique to subpopulations of cells. Within a tissue, permeability of epithelia is precise and governed by the spaces between closely packed clusters. These intercellular spaces, tight junctions, control paracellular transport of media inherent to a particular tissue.
Tight junctions are multiprotein complexes formed via cytosolic signaling and scaffold proteins, and integral membrane-spanning proteins. Tight junctions permit epithelia to perform three critical functions: 1) form permselective barriers, separating internal body compartments; 2) maintain cell polarity, giving distinct properties to plasma membrane domains (fence); and 3) create paracellular pores, selectively allowing passage of ions and solutes between sheets. To achieve such an array of responsibilities, tight junctions must possess numerous yet unidentified characteristic features. What dictates observed variability in epithelial tight junction permeability, selectivity, and structure remains largely uncharacterized. Research in the Vecchio Lab intends to elucidate tight junction structure−function in molecular level detail by combining state-of-the-art quantitative biochemical and biophysical approaches with structural biology. Such detailed examination is essential to understand the barrier, pore, and fence functions of epithelia, and the roles tight junctions play in regulating the rate-limiting step of paracellular transport, which render epithelium distinct whilst modulating tissue homeostasis.
(A) Epithelial tissues are held together at apical surfaces by tight junctions, macromolecular complexes that organize in novel ways to direct paracellular transport of solutes between cell sheets. (B) Claudins, a family of integral membrane proteins, reside at tight junctions and impart permeability to epithelium, creating a barrier or size/charge−selective pore. (C) Normally, tissue-specific expression of claudins results in highly-regulated movements of molecules through paracellular space, with accompanying fortification of cell-cell contacts. (D) Under certain physiological conditions or during disease processes, large or small molecules can disrupt vital claudin interactions, resulting in unregulated paracellular transport via tight junction dissociation. This research aims to elucidate tight junction formation and deformation at the molecular level, helping to clarify our understanding of tight junction structure−function and the biomolecular mechanisms that cause tight junction disruptions and lead to human disease.