FGF10 regulation of lung branching morphogenesis

Boston University Medical Campus, Boston MA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Experiments in this proposal focus on the mechanisms by which FGF10 determines the pattern of epithelial budding and airway branching. Our previous studies defined the sites of expression and characterized the functions of FGF10 in the lung in vivo. Since the sites where epithelial buds will form is determined by the expression of FGF10, it is critical to understand what regulates the FGF10 promoter and protein expression. We have begun studies to clone the FGF10 promoter which we will use for standard promoter analyses in vitro and in vivo. Once FGF10 is expressed, it appears to bind to its receptor in a spatial pattern that differs from that of FGF7 and induces cellular events that differ from those of FGF7. We will use these differences to compare and contrast FGF10 and FGF7 ligandreceptor interactions, receptor-mediated signaling, and downstream target activation. We will characterize differences in FGF10 and FGF binding to FGFR2b, focusing on the role that cell surface heparin sulfate proteoglycans (HSPG) play in ligand selectivity. We will identify the signaling pathways activated by FGF10 and FGF7 through FGFR2b and determine the role played in regulation of signaling by the epithelial cell LAR tyrosine phosphatase, a protein we have studied extensively. We will define FGF10-specific, epithelial target genes and examine their roles in initiation of airway branching in the embryonic lung. We will prioritize these studies, in an hypothesis-driven analyses of fetal lung explants, focusing on expression of genes potentially related to metabolism of matrix at the sites of airways branching. Finally, using a discovery-driven approach, we will employ cDNA gene expression arrays to explore the spectrum of changes in gene expression that distinguish the molecular responses to exogenous FGF10 from those of FGF7 in mesenchyme-free fetal epithelium.