I am interested in long, sugar-rich, chatty molecules (mucins) and their interaction with other molecules and cells. Recent work has focused on the sugar groups at the surface of a gel, which modulate bacterial and immune cell binding to that surface.
Research keywords: AFM, glycobiology, mucins, nanoparticles, ocular surface, saliva, toxicology in vitro
Tel. No.: +44 (0)117 39 40014
A soft mucus gel coats and protects the surfaces of wet epithelia where the body encounters its environment: the surfaces of eye, mouth, nose, respiratory and digestive systems, and more. Mucins, very large molecules whose peptide core is richly decorated with sugars, form the backbone of these mucus gels, where they interact with bacteria and viruses on the one hand, and with epithelial cells and cells of the immune system on the other.
Along the peptide core, sugars chains are very dense in places, and sparse in others, giving a mucin the appearance of a necklace of pearls (as shown, left, for a more than 5 µm long human ocular mucin molecule imaged by Atomic Force Microscopy). Epithelial mucins come in two flavours, secreted (like the example, left), and cell surface bound. The mucin subunit of the latter (below, right) is cleaved into the overlying fluid. Mucins spanning the cell membrane convey information to the inside of the cell.
Changes in mucins are associated with disease in some organs e.g. breast and colon – MUC1, the first mucin discovered, has been the focus of research for its connection with breast cancer. In very severe dry eyes there is a decrease in goblet cells, cells which synthesise, store and secrete MUC5AC.
Sugar chains, in particular the last or last few sugars in the chain, are what a microorganism sees on a mucin molecule or gel: bacteria and viruses are very choosy in their sweet epitopes. An alteration in the charge or type of sugars can have a large effect on the resident microflora.
The general structure of mucins is conserved throughout the body, yet details are tuned to the site of secretion. For example, gastric mucins have long oligosaccharide chains, while at the ocular surface sugar chains are short.
The lynch-pin of my research has been understanding how the behaviour of molecules in a complex fluid is affected by alterations in their biophysical and biochemical characteristics. The complexity of molecular behaviour has prompted collaborations with other mucineers, especially Tony Corfield, physicists(1 & 2), (sugar) biochemists(3, 4, & 5), microbiologists(6), optometrists(7), and clinicians(8, 9, & 10).
A collaboration with the cosmetics industry on alternative methods for toxicity testing, has resulted in the development of a three-dimensional corneal model. Further to classical toxicology assays we characterised the cytokine secretion of the construct which was stable in controls and specifically altered after exposure to toxicants.
An newer interest is models to study nanoparticle toxicity in the light of their potential as a research tool and therapeutic modality.
Secreted ocular mucin imaged in HEPES buffer with NiCl2 by AFM (TJ McMaster).
The higher regions of the molecule (here darker blue) are regions of high glycosylation, and at most 1.5 nm above the mica substrate
Muc4 (gift from Kermit Carraway) on graphite, imaged in HEPES buffer with NiCl2 and 0.01% Tween 20, by AFM (D Brayshaw).
Organ-cultured cornea (left) and 3D corneal model (right) where epithelial cells grown on a collagen gel seeded with human corneal fibroblasts.
Marcus Radburn Smith and Berry (unpublished results)