Research

Researches into novel functions of HGF and promotion of clinical application of HGF

The Project Leader's Profile

Toshikazu Nakamura

Ph.D., Specially Appointed Professor, Professor Emeritus of Osaka University
Joint Research Division for Regenerative Drug Discovery, Center for Advanced Science and Innovation, Osaka University

In 1972, completed the doctoral course at Osaka University Graduate School of Science and obtained his Ph.D. In 1980, appointed as Associate Professor at School of Medicine, University of Tokushima. In 1988, Professor at Faculty of Science, Kyushu University. In 1993, Professor at Biomedical Research Center, Osaka University Medical School. In 2001, Professor at Molecular Regenerative Medicine, Osaka University Graduate School of Medicine. From 2008, he holds the current position. Specialized in biochemistry, molecular biology and regenerative medicine, especially in analysis of the mechanisms of organ regeneration by HGF and its clinical application. Major publications include 'Experimental Procedure for Primary Cultured Hepatocytes' and 'Molecular Medicine of HGF'. He has received Princess Takamatsu Cancer Research Award, Academic Award of the Mochida Memorial Foundation, Osaka Science Award, Inoue Prize for Science, Nature Medicine AnGes MG Biomedical Award, Medal with Purple Ribbon, etc.

Project Leader
  • Toshikazu Nakamura (Ph.D.), Specially Appointed Professor, Joint Research Division for Regenerative Drug Discovery, Center for Advanced Science and Innovation, Osaka University
Research Members
  • Kazuhiro Fukuta, Guest Associate Professor, Joint Research Division for Regenerative Drug Discovery, Center for Advanced Science and Innovation, Osaka University
  • Kiyomasa Oka, Specially Appointed Assistant Professor, Joint Research Division for Regenerative Drug Discovery, Center for Advanced Science and Innovation, Osaka University
Research Collaborators
  • Wakana Ooya, Global COE Specially Appointed Researcher, Joint Research Division for Regenerative Drug Discovery, Center for Advanced Science and Innovation, Osaka University
  • Hiroshi Funakoshi, Associate Professor, Division of Molecular Regenerative Medicine, Osaka University Graduate School of Medicine
  • Shinya Mizuno, Assistant Professor, Division of Molecular Regenerative Medicine, Osaka University Graduate School of Medicine
  • Kunio Matsumoto, Professor, Cancer Research Institute, Kanazawa University

Summary

Liver regeneration has been known as the most dramatic phenomenon among organ regeneration in higher animals. In 1984, we identified HGF (hepatoctyte growth factor) as a substance responsible for liver regeneration. Subsequent studies revealed that HGF also acts on renal tubular epithelial cells, alveolar epithelial cells, cardiac myocytes, vascular endothelial cells and neurons, in addition to hepatocytes. HGF exerts a variety of biological activities including mitogenic, motogenic (enhancement of cell motility), morphogenic and anti-apoptotic activities. Through these activities, HGF facilitates regeneration of various tissues and organs including the liver. Currently, HGF is recognized as an endogenous repair/regeneration factor for tissues and organs.
HGF can serve as a therapeutic agent or a regenerative medicine for treatment of various diseases. Actually, we demonstrated that HGF has preventive and therapeutic effects on various diseases in experimental animals. HGF shows remarkable therapeutic effects on not only acute diseases (e.g., fulminant hepatitc failure, myocardial infarction, acute renal failure), but also chronic diseases (e.g., liver cirrhosis, chronic renal disease, lung fibrosis, cardiomyopathy) and neurodegenerative diseases (e.g., ALS). Base on this background, clinical investigations for acute renal failure (phase I) and skin ulcer (phase I/II) have started in USA and Norway/Sweden, respectively. We are extending our researches aiming at clinical application of HGF for other incurable diseases.
On the other hand, we are paying attention to novel functions of HGF. HGF is a heterodimeric protein composed of α-chain containing four kringle domains and β-chain having a serine protease-like structure. The molecular mass of the entire HGF molecule is 85 kDa, which is significantly larger than other growth factors. Recently, it was reported that chymase and elastase secreted from active mast cells and neutrophils act on HGF, which generates an intramolecular fragment of HGF α-chain. Because such intramolecular fragments of HGF still retain molecular masses comparable to other growth factors, these fragments might have some biological activities and play important roles at the sites of inflammation and tissue repair. The only known receptor for HGF is c-Met and the above-described biological activities of HGF are exerted through binding to c-Met. On the other hand intramolecular fragments derived from HGF might bind to a novel receptor different from c-Met. We are investigating novel functions of HGF through identification of such novel receptor(s) for HGF fragments.

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Some of Recent Papers

  1. Matsumoto K, Nakamura T, Sakai K, Nakamura T. Hepatocyte growth factor and Met in tumor biology and therapeutic approach with NK4. Proteomics. 8: 3360-3370, 2008.
  2. Ohnishi H, Mizuno S, Nakamura T. Inhibition of tubular cell proliferation by neutralizing endogenous HGF leads to renal hypoxia and bone marrow-derived cell engraftment in acute renal failure. Am. J. Physiol .Renal Physiol. 294: F326-335, 2008.
  3. Ohya W, Funakoshi H, Kurosawa T, Nakamura T. Hepatocyte growth factor (HGF) promotes oligodendrocyte progenitor cell proliferation and inhibits its differentiation during postnatal development in the rat. Brain Res. 1147, 51-65, 2007.
  4. Matsumoto K, Nakamura T. Hepatocyte growth factor and the Met system as a mediator of tumor-stromal interactions. Int. J. Cancer. 119, 477-483, 2006.
  5. Machide M, Hashigasako A, Matsumoto K, Nakamura T. Contact inhibition of hepatocyte growth regulated by functional association of the c-Met/hepatocyte growth factor receptor and LAR protein-tyrosine phosphatase. J. Biol. Chem. 281, 8765-8772, 2006.