The primary objective of the proposed research is to investigate the morphoregulatory role of glucocorticoids (CORT) during embryonic salivary gland development. Published and preliminary studies indicate that CORT, with its receptor (GR) regulate salivary gland branching and histodifferentiation by regulating specific growth and developmental factors. This proposal will use an in vitro model system to test the hypotheses that (1) CORT-GR-mediated expression of specific growth factors/receptors (TGF-b, TNF-a, or EGF-R) is a key molecular mechanism regulating morphodifferentiation and histodifferentiation of the embryonic salivary gland; (2) CORT-GR modulation of Msx2 expression at sites of epithelial-mesenchymal interaction plays a critical role during embryonic salivary gland morphogenesis; and (3) CORT-GR mediated enhancement of epithelial cell proliferation is most likely via one or more TGF-b..cyclin-cdk and/or TGF-b..N-myc pathway(s).
The specific aims are to: (1) elucidate the molecular mechanism of CORT-GR-mediated embryonic submandibular gland morphoregulation; (2) to investigate the molecular details of CORT-modulated Msx2-mediated embryonic submandibular gland morphogenesis, and (3) to investigate the roles of TGF-b2, TGF-b3, p27, cdk4, cyclin E and N-myc in CORT-GR modulation of epithelial cell proliferation and branching morphogenesis. The data generated will delineate molecular mechanisms of CORT-GR mediated morphoregulation of embryonic submandibular gland development and identify relevant morphoregulatory pathway(s) to be investigated in subsequent in vivo studies. Since salivary glands continue to develop after birth, these studies may eventually provide new insights into novel hormone, growth factor, or other treatment strategies for congenital anomalies of structure or function. Such treatment strategies may even be useful in treating adult salivary gland disease.
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