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SALIVARY MUCIN, SYNTHESIS, PROCESSING AND SECRETION

唾液粘蛋白、合成、加工和分泌

基本信息

批准号：
6175811
负责人：
PAUL C DENNY
金额：
$ 26.22万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-08-01 至 2002-05-31
项目状态：
已结题

项目摘要

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.

唾液粘蛋白是一类糖蛋白，其生物活性范围从保护性涂层的形成到聚集和/或失活病毒和口腔细菌的特定菌株。的最终目标该项目旨在为开发治疗方法提供理论基础，逆转唾液腺和唾液中粘蛋白的损失，在人类和小鼠中伴随衰老。理解基本的围绕粘蛋白合成和糖基化的过程是揭示与衰老有关的损失的根源，适当的治疗反应。将用于粘蛋白产生的本研究的模型系统使用年轻成年小鼠的下颌下腺和舌下腺。两个腺体是因为每一种都产生独特的粘蛋白。这些粘蛋白似乎是类似于人唾液粘蛋白MG 1和MG 2。此外该每种粘蛋白的分泌都受到不同的调节，这是一个评估粘蛋白分泌和恢复的机会，主要作为胆碱能或β-肾上腺素能反应有了这些系统，转录、区室化和将测量粘蛋白mRNA的稳定性。Apomucin合成和糖基化也将在分泌之前和之后进行评估，用于比较年轻和老年小鼠中粘蛋白恢复率的基线。在初步的研究中，已经表明，在两种细胞中的粘蛋白产生都是由细胞内的粘蛋白产生的。腺体可以通过慢性过度刺激方案上调。这粘蛋白的上调也可以在衰老小鼠中完成，比年轻老鼠体内的水平更高。然而，目前尚不清楚这是否逆转衰老效应的方法是适当的，与衰老有关的损失。因此，该项目的后续方面将集中精力更好地了解哪些粘蛋白生产过程随着老化而下降，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开发了这些包括两种粘蛋白以及针对脱粘蛋白及其完全糖基化对应物的抗血清。这些将用于定量粘蛋白及其mRNA。的系统对N-和O-连接寡糖进行定量和测序将也被雇用。下颌下和舌下粘蛋白cDNA克隆和一个唾液细胞特异性蛋白P2 O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以证明它们的相关性和/或可能的基因多态性。