During the past year, we have continued to focus our research efforts on the study of a secreted, Frizzled-related protein (sFRP-1) that is thought to have an important role in embryonic development and perhaps neoplasia. We developed an abundant source of recombinant sFRP-1 to demonstrate that it can bind directly to Wnt protein and exert a biphasic effect on Wnt activity. Several collaborative studies with recombinant sFRP-1 are broadening our understanding of its biological activity. In a rat embryonic kidney organ culture, sFRP-1 can block tubulogenesis presumably by inhibiting Wnt-4 activity. Preliminary results suggest that sFRP-1 alters the behavior of stem cells from the rat central nervous system and microvascular endothelial cells from rat kidney. We also have been investigating sfrp-1 gene structure and characterizing its promoter activity to better understand how its expression is regulated.Substantial progress has been made in an ongoing collaboration concerning the structure-function analysis of HGF/SF. NMR solution studies involving the amino-terminal domain and heparin or heparin analogs have yielded new information about the primary heparin-binding site of HGF/SF. Additional experiments are in progress to confirm the identity of the amino acid residues responsible for heparin-binding, and to determine the consequences of their replacement with residues that will not mediate heparin interactions. Collaborative studies have yielded new information about the activity of keratinocyte growth factor (KGF or FGF-7). In particular, KGF was shown to stimulate the growth of spiral arteries in primate uterus, which could be important for the establishment of fetal-maternal circulation. Other ongoing investigations concern the role of KGF/KGFR signaling in thymus development and T cell maturation, and the mechanisms responsible for KGF?s ability to ameliorate the impact of graft versus host disease associated with bone marrow transplantation. - cell proliferation, growth factor, HGF/SF, protein function, receptor, Wnt signaling, Frizzled, KGF,
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