Membrane Bound Mucins in Salivary Glands and Saliva

描述(申请人提供)：粘蛋白是一种高度糖基化的蛋白质，由胃肠道、呼吸道和泌尿生殖道内的上皮细胞分泌。已鉴定出两种截然不同的粘蛋白，凝胶形成粘蛋白和分泌型粘蛋白。在口腔中，形成凝胶的粘蛋白促进说话和吞咽，保护口腔表面，并有助于在底层上皮细胞和外部环境之间形成选择性渗透的扩散屏障。我们已经证明，唾液腺和口腔上皮细胞也表达膜粘蛋白，并提出这些粘蛋白可能在口腔上皮细胞表面形成支架，形成凝胶的粘蛋白和其他唾液蛋白可以选择性地结合在支架上。结合可以将这些蛋白质集中在特定的区域，并可以延长它们在口腔中的停留时间。这种支架很可能是口腔宿主防御系统的关键组成部分，以保护上皮表面免受细菌、化学和机械损伤。膜结合的粘蛋白包含两个非共价结合的亚基：一个粘蛋白样胞外亚单位和一个参与细胞内信号转导的胞内亚基。我们在这个应用中的假设是，支架中结合在膜上的粘蛋白作为受体分子发挥作用，将有关细胞外部条件的信息转化为基因表达的变化和宿主反应的激活。这一过程可能涉及膜结合的粘蛋白和支架的其他成分之间的特定相互作用。这一应用的具体目的是：1)研究膜结合粘蛋白和分泌的唾液粘蛋白之间的相互作用；2)鉴定与膜结合粘蛋白形成复合体的非粘蛋白蛋白并绘制相互作用区域图；3)表征粘蛋白支架的所有成分在细菌损伤模型中的作用；4)研究这两个粘蛋白亚基在感受细菌挑战和激活细胞内信号通路方面的功能能力。这一应用主要集中在口腔上皮细胞表面有序粘蛋白支架的表征及其与口腔细菌的相互作用。这些相互作用可能代表着治疗或预防口腔感染和牙周病的新的治疗靶点。

DESCRIPTION (provided by applicant): 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 signaling. Our hypothesis in this application 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 application 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 signaling pathways. This application 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.