| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2001: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
HGF activator inhibitor (HAI-1) is a proteinaceous inhibitor of HGF activator (HGFA), which proteolytically activates hepatocyte growth factor (HGF). HGF is a multifunctional cytokine that is involved in regeneration and tissue repair after injury. HAI-1 is synthesized as a type I membrane protein, and secreted as a 40 kD HAI-1 or 58 kD HAI-1 by proteolytic processing. 40kD HAI-1 contains one Kunitz domain (Kunitz 1), whereas 58 kD HAI-1 contains two Kunitz domains (Kunitz 1 and 2). We generated deletion mutants of each Kunitz domains, and found that Kunitz 1is mainly involved in inhibition of HGFA. Although 58 kD HAI-1contains two Kunitz domains, its inhibitory activity for HGFA is very weak. We found that two Kunitz domains masked each other, thus lowering the inhibitory activity of the whole protein.
When two-thirds of rat liver is resected, pro-HGF in the residual liver increases dramatically, but the active HGF is present in only a small amount. We then administered active HGFA via portal vein 24 h after partial hepatectomy, and examined the effect on liver regeneration. Administration of HGFA caused activation of pro-HGF in the residual liver and induced tyrosine phosphorylation of c-Met (HGF receptor). In addition, labeling index of hepatocytes was increased, and recovery of liver mass was promoted. We needed, however, a large amount of HGFA to obtain significant enhancement of liver regeneration, indicating that tissue-derived inhibitors such as HAI-1 play important roles in regulating activity of HGFA in vivo.
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