The candidate proposed to study the role of the anti-adhesive molecule SPARC (Secreted Protein Acidic and Rich in Cysteine) in the regulation of branching morphogenesis of airways during fetal rat lung development. Through the process of branching morphogenesis the complex network of conducting airways is formed. Epidermal growth factor (EGF) has been shown to stimulate this process. Anti-adhesive molecules could play a role in this process by altering epithelial cell shape and adhesion to the surrounding matrix and thus facilitating migration. Our preliminary studies have shown extensive expression of SPARC in fetal rat lung by immunocytochemistry and in situ hybridization with SPARC mRNA. Pilot studies also suggest that EGF stimulates an increase in SPARC mRNA levels in cultured fetal rat lung fibroblasts, as well as in fetal lung explants. We hypothesize that the stimulatory effects of EGF on branching morphogenesis are mediated in part through a stimulation of SPARC production.
Our Specific Aims are as follows: (1) To determine the cellular and biochemical mechanisms through which SPARC influences branching morphogenesis; (2) To determine the effects of EGF on the production of SPARC by fetal lung fibroblasts and epithelial cells; (3) To study the relationship of SPARC and EGF in regulating branching morphogenesis; (4) To study the effects of SPARC and EGF on epithelial cell migration and proliferation, and to determine whether EGF effects on epithelial cell migration and proliferation are mediated by SPARC. These studies are expected to elucidate the role of SPARC in lung development and to identify the mechanisms whereby it exerts its biological effects.
| Strandjord, T P; Madtes, D K; Weiss, D J et al. (1999) Collagen accumulation is decreased in SPARC-null mice with bleomycin-induced pulmonary fibrosis. Am J Physiol 277:L628-35 |
| Hormuzdi, S G; Strandjord, T P; Madtes, D K et al. (1999) Mice with a targeted intronic deletion in the Col1a1 gene respond to bleomycin-induced pulmonary fibrosis with increased expression of the mutant allele. Matrix Biol 18:287-94 |
