Mucins are heavily glycosylated proteins which are secreted by epithelial cells lining the gastrointestinal, respiratory and genitourinary tracts. Two distinct classes of mucins have been identified, gel forming mucins and secreted mucins. In the oral cavity, gel forming mucins facilitate speech and swallowing, protect oral surfaces, and contribute to a selectively permeable diffusion barrier between underlying epithelia and the external environment. We have shown that membrane mucins are also expressed in salivary glands and oral epithelia and have proposed that these mucins may form a scaffold on oral epithelial surfaces to which gel forming mucins and other salivary proteins can selectively bind. Binding could serve to concentrate these proteins in specific regions and could prolong their residence time in the oral cavity. It seems likely that the scaffold would be a key component of the oral host defense system in protection of epithelial surfaces from bacterial, chemical and mechanical injury. Membrane bound mucins contain two non-covalently associated subunits: a mucin-like extracellular subunit and a cytoplasmic subunit which is involved in intracellular signalling. Our hypothesis in this proposal is that the membrane bound mucins in the scaffold function as receptor molecules, translating information about conditions on the outside of the cell into changes in gene expression and activation of a host response. This process likely involves specific interactions between membrane bound mucins and other components of the scaffold.
The Specific Aims of this proposal are to: 1) investigate interactions between membrane bound mucins and secreted salivary mucins, 2) identify non- mucin proteins which form complexes with membrane bound mucins and map the interacting domains, 3) characterize the role of all components of the mucin scaffold in a model of bacterial injury and 4) investigate the functional capacity of role of both mucin subunits in sensing a bacterial challenge and activation of intracellular signalling pathways. This proposal is focused on the characterization of the ordered mucin scaffold on the surface of oral epithelial cells and its interactions oral bacteria. These interactions may represent new therapeutic targets to treat or prevent oral infections and periodontal disease.
