SALIVARY MUCIN, SYNTHESIS, PROCESSING AND SECRETION

唾液粘蛋白是一类生物活性范围广泛的糖蛋白。 从保护膜的形成到聚集和/或失活 特定的病毒株和口腔细菌。的最终目标是 该项目旨在为开发治疗方法提供理论基础 扭转唾液腺和唾液中粘蛋白的损失，如观察到的 伴随着人类和小鼠的衰老。对根本问题的理解 围绕粘蛋白合成和糖基化的过程是 揭示与衰老相关的损失的起源和发展 适当的治疗反应。 将用于粘蛋白生产研究的模型系统 使用幼年成年小鼠的颌下腺和舌下腺。两个腺 之所以包括在内，是因为每种都会产生一种独特的粘蛋白。这些粘蛋白似乎是 类似于人类唾液粘蛋白，MG1和MG2。此外， 每种粘蛋白的分泌受到不同的调节，提供 评估粘蛋白分泌和恢复的机会，即 主要作为胆碱能或β-肾上腺素能引起 回应。有了这些系统，转录、划分和 将测量粘蛋白mRNAs的稳定性。Apomucin的合成和 糖基化也将在分泌前后进行评估，以提供 比较年轻和老年小鼠粘蛋白回收率的基线。 在初步研究中，已经表明，在两种情况下，粘蛋白的产生 腺体可以通过一种慢性过度刺激的养生法来上调。这 在衰老的小鼠体内也可以实现粘蛋白的上调 达到比幼鼠更高的水平。然而，目前还不清楚这是否会 逆转衰老效应的方法是适当的还是潜在的 年龄相关损失的原因。因此，该项目的后期方面 将专注于更好地了解哪些粘蛋白 生产过程随着年龄的增长而下降，哪些过程是 对过度刺激的反应上调。 为了实现上述目标，分子和免疫学探针已经 已经被开发出来了。这些克隆包括粘蛋白和 抗无蛋白粘蛋白及其完全糖基化的抗血清。 这些将被用来定量粘蛋白及其mRNAs。一种系统，用于 对N-和O-连接的寡糖进行定量和测序将 也会被雇佣。颌下腺和舌下腺粘蛋白基因克隆及 唾液细胞特异性蛋白P2O的cDNA克隆 与粘蛋白的序列同源性也将用于探测小鼠基因组 寻找它们的关联性和或可能的基因多态的证据。

Mucins from saliva are a class of glycoproteins whose bioactivities range from formation of protective coatings to aggregation and/or inactivation of specific strains of viruses and oral bacteria. The ultimate goal of this project is to provide a rationale for developing treatments to reverse losses of mucin from salivary glands and saliva such as observed to accompany aging in humans and mice. An understanding of the fundamental processes surrounding mucin synthesis and glycosylation is the key to revealing the origins of the aging-related losses and to development of appropriate treatment responses. The model systems that will be employed for this study of mucin production use the young adult mouse submandibular and sublingual glands. Both glands are included because each makes a unique mucin. These mucins appear to be analogous to the human salivary mucins, MG1 and MG2. In addition, the secretion of each mucin is regulated differently, providing the opportunity for evaluating the secretion and restitution of mucin that is elicited either primarily as a cholinergic or as a beta-adrenergic response. With these systems, transcription, compartmentalization and stability of mucin mRNAs will be measured. Apomucin synthesis and glycosylation will also be evaluated before and after secretion to provide a baseline for comparison of mucin recovery rates in young and aged mice. In preliminary studies, it has been shown that mucin production in both glands can be upregulated by a regimen of chronic hyperstimulation. This upregulation of mucin can also be accomplished in senescent mice leading to levels higher than in young mice. However, it is not known if this approach to reversing the aging effect is appropriate or the underlying cause of the aging-related loss. Thus, the later aspects of this project will focus on gaining a better understanding of which of the mucin production processes decline with aging and which processes are upregulated in response to hyperstimulation. To accomplish the above goals, molecular and immunological probes have been developed. These include cDNA clones for both mucins as well as antisera against both apomucins and their fully glycosylated counterparts. These will be used to quantitate the mucins and their mRNAs. A system for quantitating and sequencing both N- and O-linked oligosaccharides will also be employed. The submandibular and sublingual mucin cDNA clones and a cDNA clone for a salivary cell-specific protein, P2O, that shows sequence homology with mucins will also be used to probe the mouse genome for evidence of their relatedness and or possible gene polymorphism.