Saliva is critical to the maintenance of oral health. A future goal of salivary gland research is the development of treatment therapies to replace lost or damaged salivary secretory tissue, possibly through gene therapy and/or tissue engineering. The success of either approach is likely to depend on a thorough understanding of the role of transcription factors in salivary gland development and gene expression. To date, although great progress has been made in understanding the physiological basis for salivary secretion, little is known about the regulation of salivary gland-specific gene expression. The focus of this proposal is to understand the regulation of gene expression in submandibular proacinar cells, a transient intermediate cell type in the pathway to the seromucous acinar cells of the adult gland. The developmentally regulated secretory proteins, Smgb and Csp-1, are produced by submandibular proacinar cells, as well as by immature parotid acinar cells and by sublingual serous demilunes. The hypotheses underlying this proposal are that (a) expression of Smgb, Csp-1 and the other proacinar cell proteins is regulated by a combination of generally expressed and salivary-specific transcription factors, (b) some of these salivary-specific transcription factors are shared by the submandibular, sublingual and parotid glands, and (c) these shared factors are also important for salivary gland development. There are three specific aims.
Aim 1 is to identify proacinar cell-specific enhancers of Smgb and Csp-1 gene expression. Enhancers will be delineated by testing portions of these developmentally regulated salivary protein genes or hgh fusion genes derived from them for expression in transgenic mice. Transcription factor binding sites will be identified by DNA sequence analyses and protein binding assays.
Aim 2 is to isolate and characterize cDNA clones encoding transcription factors present in the neonatal submandibular gland. Clones will be identified by homology to known transcription factor families, and/or by interaction of proteins they encode with specific enhancer binding sites determined as outlined in aim 1.
Aim 3 is to determine the gland- and cell-specificity of salivary transcription factors throughout development. Salivary gland transcription factors identified from the literature, or isolated as described in Aim 2, will be localized by immunocytochemistry.
Showing the most recent 10 out of 12 publications
