Matrix Ga protein (MGP), a vitamin K-dependent protein first isolated from the matrix of bone, is also abundant in developing and adult lung. Although its function in any tissue is unknown, we have recently obtained evidence that MGP restricts embryonic lung branching and alveolar sac formation in a spatial and temporal manner. Treatment of day 14 rat lung explants with MGP antibodies doubles the number of terminal lung buds that are formed during culture. Addition of vitamin K to explants stimulates the carboxylation and secretion of mature MGP in the distal aspects of the lung and restricts normal branching and budding. Other factors that influence morphogenesis and adult lung growth, including retinoic acid, dexamethasone, TGF-beta and EGF also have an appropriate influence on MGP expression. That is, when MGP is increased, growth is restricted. We propose to study the expression of MGP in both epithelial and mesenchymal compartments of developing lungs using both explant and isolated cell models to establish that MGP is a key modulator of morphogenesis and is a common mediate of the above mentioned factors. Manipulation of the expression of MGP will identify strategies to increase alveolization during development and in adult lung. These studies will employ the use of antibody and anti-sense RNA blocking strategies, peptide competition and protein addition protocols, and the selective administration of growth factors and agents into mesenchymal and epithelial compartments of the lung. We will also selectively restrict vitamin K function in the lung to allow growth to accelerate in the absence of MGP. This approach will incorporate a combination of treatment protocols which should optimize differentiation and growth and focus on autocrine and paracrine relationships in MGP action. The hypothesis of the of these studies is that MGP is tightly regulated in a cell-specific and temporal manner to restrict growth and alveolization in developing and adult lung. It's expression, and therefore function, is tightly controlled by numerous growth-promoting and restricting factors.
| Gilbert, Kirk A; Rannels, Stephen R (2004) Matrix GLA protein modulates branching morphogenesis in fetal rat lung. Am J Physiol Lung Cell Mol Physiol 286:L1179-87 |
| Gilbert, Kirk A; Rannels, Stephen R (2003) Glucocorticoid effects on vitamin K-dependent carboxylase activity and matrix Gla protein expression in rat lung. Am J Physiol Lung Cell Mol Physiol 285:L569-77 |
| Brown, L M; Welch, D R; Rannels, S R (2002) B16F10 melanoma cell colonization of mouse lung is enhanced by partial pneumonectomy. Clin Exp Metastasis 19:369-76 |
| Brown, L M; Rannels, S R; Rannels, D E (2001) Implications of post-pneumonectomy compensatory lung growth in pulmonary physiology and disease. Respir Res 2:340-7 |
