Salivary gland dysfunction secondary to radiation therapy or to inflammatory disease results primarily from damage to the salivary gland acinar cells. These cells are the sites of salivary protein biosynthesis and secretion, and of fluid and electrolyte transport into the primary saliva. Salivary acinar cells undergo constant replacement, at least partially by maturation of progenitor cells located in the intercalated ducts. An understanding of the regulation of this intercalated duct to acinar cell transition could lead to directed acinar cell replacement therapy for individuals with appropriate types of salivary gland damage. We will use the neonatal rat and mouse submandibular gland as a model to study acinar cell maturation. The type III or proacinar cells of the neonatal rat submandibular gland are progenitors to the seromucous acinar cells of the mature gland. These cells produce several developmentally regulated secretory proteins that are not expressed by the acinar cells of the adult submandibular gland, but are present in a subset of intercalated duct cells phenotypically similar to the neonatal type III cells. It has been hypothesized that these intercalated duct cells are the progenitors for acinar cell replacement in the adult gland. The goal of the experiments described in this proposal is to understand the regulation of gene expression in the neonatal type Ill cells, and in their phenotypic counterparts in the intercalated ducts. We will: l. Complete ongoing characterization of the major products of the neonatal submandibular gland. 2. Determine whether these genes are also expressed in the sublingual and parotid glands, using a combination of molecular biological and immunocytochemical methods. 3. Isolate and characterize genomic DNA containing the structural genes and upstream regulatory regions for neonatal submandibular gland proteins SMG-A and CSP1. 4. Demonstrate the ability of these regulatory regions to direct appropriate cell specific gene expression in transgenic mice. The reporter gene used will be SV4O T antigen, a potent oncogene. Salivary tumors derived from T antigen expression will be used to establish cell lines for further studies of SMG-A and CSP1 gene expression.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Oral Biology and Medicine Subcommittee 1 (OBM)
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University of California Berkeley
Schools of Arts and Sciences
United States
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Zinzen, Karen M; Hand, Arthur R; Yankova, Maya et al. (2004) Molecular cloning and characterization of the neonatal rat and mouse submandibular gland protein SMGC. Gene 334:23-33
Ball, W D; Mirels, L; Hand, A R (2003) Psp and Smgb: a model for developmental and functional regulation in the rat major salivary glands. Biochem Soc Trans 31:777-80
Wolff, M S; Mirels, L; Lagner, J et al. (2002) Development of the rat sublingual gland: a light and electron microscopic immunocytochemical study. Anat Rec 266:30-42
Hecht, R; Connelly, M; Marchetti, L et al. (2000) Cell death during development of intercalated ducts in the rat submandibular gland. Anat Rec 258:349-58
Dardick, I; Ho, J; Paulus, M et al. (2000) Submandibular gland adenocarcinoma of intercalated duct origin in Smgb-Tag mice. Lab Invest 80:1657-70
Gupta, N; Asp, E; Levan, G et al. (2000) Structure and chromosomal localization of the rat salivary Psp and Smgb genes. Gene 243:8-Nov
Mirels, L; Miranda, A J; Ball, W D (1998) Characterization of the rat salivary-gland B1-immunoreactive proteins. Biochem J 330 ( Pt 1):437-44
Mirels, L; Hand, A R; Branin, H J (1998) Expression of gross cystic disease fluid protein-15/Prolactin-inducible protein in rat salivary glands. J Histochem Cytochem 46:1061-71
Sivakumar, S; Mirels, L; Miranda, A J et al. (1998) Secretory protein expression patterns during rat parotid gland development. Anat Rec 252:485-97
Hand, A R; Sivakumar, S; Barta, I et al. (1996) Immunocytochemical studies of cell differentiation during rat salivary gland development. Eur J Morphol 34:149-54

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