The investigator has identified and characterized a human and rodent gene for which the cDNA codes for a protein with a domain structure similar to hepatocyte growth factor (HGF). The derived protein contains four kringle domains, followed by a serine protease-like domain, and has been termed """"""""HGF-like protein."""""""" Although the biologic properties of HGF as a mitogen, motogen and morphogen have been described, as well as growth suppressor function in some cell lines, the biologic properties of HGF-like protein have not yet been defined. In contrast, the HGF, which is expressed in many cell types including liver non-parenchymal or Ito cells, HGF-like protein as studied to date, is expressed primarily or at much higher levels in hepatocytes as compared to other tissues and is actively secreted into the circulation. Sequencing data has shown that this protein is identical to macrophage stimulating protein (MSP), and a cell surface tyrosine kinase receptor for HGF-like protein, referred to as Ron, has been identified. In contrast to the HGF-receptor, c-Met, which is also a cell surface tyrosine kinase, Ron is not expressed on hepatocytes. From these studies, Dr. Degen hypothesizes that HGF-like protein has diverse biologic properties similar to HGF, but exerts its effects on a different set of cell types. To test this hypothesis, she proposes the following specific aims: 1) to determine the cellular site(s) of synthesis and identification of cell lines expressing the Ron receptor; 2) to determine the mitogenic, chemotactic and motility properties of HGF-like protein using Ron expressing cell lines; 3) structure-function analysis of domains in HGF-like protein and the Ron receptor; and 4) to determine whether overexpression of HGF-like protein has a physiologic effect on Ron expressing tissue in the mouse. Ron expressing cell lines will be identified and used to determine the various biological properties of HGF-like protein. Structure-function studies will identify domain(s) responsible for specific functions and to determine whether different biological responses are elicited in a similar or different manner. The biological functions of HGF-like protein will be further investigated in normal and transgenic mice overexpressing HGF-like protein by studying models of liver regeneration, inflammation, wound healing and the acute phase response. These studies will determine the diversity of the biological properties of HGF-like protein and whether it is a growth factor with limited or broad specificity.
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