The health of the oral cavity is maintained by salivary secretions. Our past studies focused on understanding mechanisms of saliva formation, their alteration during pathology, and developing novel methods to treat salivary dysfunction. During this reporting period we continued to utilize gene transfer technology to alter salivary epithelial cells to address clinical and biological questions. Specifically, we focused on two major problems resulting from use of recombinant adenoviral vectors: transient transgene expression and a potent immune response. To extend expression we have used recombinant adeno-associated virus vectors, and developed a unique hybrid vector incorporating both adenoviral and retroviral elements. Both approaches lead to more stable expression in rodent glands. Two ways to manipulate the immune response were tried; a drug, clodronate, to deplete glands of phagocytic cells, and coadministration of vectors encoding either IL-4 or IL-10. Both methods were unsuccessful. We showed that transgenes contain sorting signals recognized by glands in vivo, that lead to specific patterns of polarized protein secretion. We also made progress towards the development of an orally implantable, first generation artificial salivary gland. - salivary glands, gene therapy, adenovirus, AAV, hybrid vectors, radiation damage, Sjogren's syndrome, secretion, biomimetics

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Intramural Research (Z01)
Project #
1Z01DE000336-18
Application #
6289664
Study Section
Special Emphasis Panel (GTTB)
Project Start
Project End
Budget Start
Budget End
Support Year
18
Fiscal Year
1999
Total Cost
Indirect Cost
Name
National Institute of Dental & Craniofacial Research
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Zheng, Changyu; Baum, Bruce J (2008) Evaluation of promoters for use in tissue-specific gene delivery. Methods Mol Biol 434:205-19
Adriaansen, Janik; Perez, Paola; Goldsmith, Corine et al. (2008) Differential sorting of human parathyroid hormone after transduction of mouse and rat salivary glands. Hum Gene Ther :
Cotrim, Ana P; Baum, Bruce J (2008) Gene therapy: some history, applications, problems, and prospects. Toxicol Pathol 36:97-103
Samuni, Yuval; Zheng, Changyu; Cawley, Niamh X et al. (2008) Sorting of growth hormone-erythropoietin fusion proteins in rat salivary glands. Biochem Biophys Res Commun 373:136-9
Zheng, Changyu; Vitolo, Joseph M; Zhang, Weitian et al. (2008) Extended transgene expression from a nonintegrating adenoviral vector containing retroviral elements. Mol Ther 16:1089-97
Samuni, Yuval; Cawley, Niamh X; Zheng, Changyu et al. (2008) Sorting behavior of a transgenic erythropoietin-growth hormone fusion protein in murine salivary glands. Hum Gene Ther 19:279-86
Nandula, Seshagiri R; Amarnath, Shoba; Molinolo, Alfredo et al. (2007) Female mice are more susceptible to developing inflammatory disorders due to impaired transforming growth factor beta signaling in salivary glands. Arthritis Rheum 56:1798-805
Yan, Xing; Voutetakis, Antonis; Zheng, Changyu et al. (2007) Sorting of transgenic secretory proteins in miniature pig parotid glands following adenoviral-mediated gene transfer. J Gene Med 9:779-87
Voutetakis, Antonis; Zheng, Changyu; Mineshiba, Fumi et al. (2007) Adeno-associated virus serotype 2-mediated gene transfer to the parotid glands of nonhuman primates. Hum Gene Ther 18:142-50
Baum, Bruce J (2007) Inadequate training in the biological sciences and medicine for dental students: an impending crisis for dentistry. J Am Dent Assoc 138:16, 18, 20 passim

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