| Research Abstract |
To develop the new treatment of liver cirrhosis in Japan, it is essential to investigate on the molecular mechanism of liver cirrhosis. In the present projects, we have concentrated in the transcriptional control mechanism and cytokine expression of tissue regeneration, because liver cirrhosis is thought to be a kind of dis-regurated morphogenesis in the liver regeneration. In the former, we have studied the effect of butyrate in alpha-fetoprotein (AFP) and albumin gene expression using the differentiated liver cancer cell lines. In the later, we have analyzed the pathophysiological role of parathyroid-hormone-related peptide (PTHrP) in morphogenesis and oncogenesis.
The study of upstream regulatory element of AFP has clarified that the CCAAT box is important in the switching mechanism from AFP to albumin gene expression. These data are speculated that the genes involving liver cirrhosis might be controlled by C/EBP (Gastroenterology 107 : 499-504,1994).
In tissue regeneration, such as l
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iver regeneration, PTHrP is a key cytokine regulated the cell motility and apoptosis (Endocrinology 134 : 1936-1942,1994. Arterioscl Throm Vascul Biol in press 1996). Increased PTHrP expression is also demonstrated to be involved the fibrosis in other organ (J Pathol 175 : 227-236, 1995). Furthermore, we have applied the antisense PTHrP oligonucleotide therapy against PTHrP producing pituitary tumor which is newly established in our laboratory (Cancer Res 56 : 77-86,1996).
To further extend the basic research, we have focused on the critical events of liver cirrhosis induced by abnormal expression of cytokines escaping from physiological regeneration or apoptosis, which can eventually induce gene instability and abnomal cell proliferation. The experimental design is in vivo rat animal model which is implanted with PTHrP producing pituitary tumor, previously described. Surprisingly, these rats are developed the liver fibrosis and splenomegaly in 3 months after tumor cell inoculation, and also developed the liver cancer 4 months after tumor implantation.
Further studies are planned on clarification of molecular mechanism of cytokine induced liver cirrhosis using This in vivo experimental systems.
Finally, we acknowledge a support from this grant and a valuable contribution of our post doc fellows and staffs. Less
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