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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE006892-15
Application #
2896934
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Project Start
1992-08-01
Project End
2001-05-31
Budget Start
1999-06-01
Budget End
2000-05-31
Support Year
15
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Southern California
Department
Dentistry
Type
Schools of Dentistry
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Baughan, L W; Robertello, F J; Sarrett, D C et al. (2000) Salivary mucin as related to oral Streptococcus mutans in elderly people. Oral Microbiol Immunol 15:4-Oct
Liu, P; Denny, P A; Denny, P (2000) The effect of ageing on parenchymal cell populations in adult female mouse submandibular gland. Arch Oral Biol 45:585-92
Denny, P C; Liu, P; Denny, P A (1999) Evidence of a phenotypically determined ductal cell lineage in mouse salivary glands. Anat Rec 256:84-90
Nowroozi, N; Denny, P A; Denny, P C et al. (1998) Two gene products for beta-galactosidase are differentially expressed in the mouse salivary glands. J Craniofac Genet Dev Biol 18:51-7
Denny, P C; Ball, W D; Redman, R S (1997) Salivary glands: a paradigm for diversity of gland development. Crit Rev Oral Biol Med 8:51-75
Denny, P C; Mirels, L; Denny, P A (1996) Mouse submandibular gland salivary apomucin contains repeated N-glycosylation sites. Glycobiology 6:43-50
Denny, P C; Denny, P A; Hong-Le, N H (1995) Characterization of asparagine-linked oligosaccharides on a mouse submandibular mucin. Glycobiology 5:589-97
Bekhor, I; Wen, Y; Shi, S et al. (1994) cDNA cloning, sequencing and in situ localization of a transcript specific to both sublingual demilune cells and parotid intercalated duct cells in mouse salivary glands. Arch Oral Biol 39:1011-22
Navazesh, M; Mulligan, R A; Kipnis, V et al. (1992) Comparison of whole saliva flow rates and mucin concentrations in healthy Caucasian young and aged adults. J Dent Res 71:1275-8
Denny, P A; Hong, S H; Klauser, D K et al. (1992) Increased mucin levels in submandibular saliva from mice following repeated isoproterenol treatment. Arch Oral Biol 37:73-5

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