This grant is in its 25th year. It was initiated at a time prior to the discovery of HGF and its receptor c-t. The studies funded through the grant led to the discovery of HGF and its receptor and provided evidence that solidified the role of HGF/Met signaling as fundamental to initiation of regeneration and tissue assembly of liver. Studies supported by this grant also led to the findings on the role of extracellular matrix, urokinase, matrix metalloproteins and plasmin during the regenerative process, liver disease and hepatic neoplasia. The proposal continues on the overall theme of growth factors (HGF) and extracellular matrix interactions, and their role in liver regeneration. We are testing the hypothesis that signals generated from hepatic extracellular matrix are important for the f termination of regeneration. ECM signaling through integrins is mediated via Integrin Linked Kinase (ILK). Liver targeted elimination of ILK results in enhanced liver size and improper termination of regeneration. ILK -/- livers gain weight (30%!) at the end of the regenerative process. Studies are proposed to further define this finding and to begin to understand the mechanisms by which ECM, acting via ILK, controls restitution of the final size of the regenerated liver to the original normal size prior to partial hepatectomy. ECM is a complex mixture of heavily substituted proteins, some truly extracellular and some anchored on the plasma membrane. In order to identify the ECM components relevant to the delivery of the regeneration termination signal, we focused on a protein known as Glypican-3 (GPC3) which is the most over-expressed protein in human liver cancer. GPC3 deletion in humans and mice results in diffuse organ over-growth (Simpson-Golabi-Behmel syndrome). GPC3 expression increases at the end of liver regeneration and at the end of a growth cycle induced by HGF and EGF in cell culture. We are exploring the hypothesis that GPC3 is the most important component of the ECM matrix termination signal and we propose to test this hypothesis by using GPC3 knockout mice and liver-targeted GPC3 transgenic mice. The above studies will continue to focus on interactive signaling between growth factors and matrix as very important in the regulation of regeneration of liver, with implications for regenerative potential in other tissues. Liver regeneration is an important aspect not only of healing liver injury, but also (when uncontrolled) in formation of cirrhosis and other forms of chronic liver damage.
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