MATSUYAMA Toshifumi Nagasaki University School of Medicine, Professor, 医学部, 教授 (30165922)
NAKAO Kazuhiko Nagasaki University Health Center, Lecturer, 保健管理センター, 講師 (00264218)
YAMASHITA Shunichi Nagasaki University School of Medicine, Professor, 医学部, 教授 (30200679)
|Budget Amount *help
¥3,700,000 (Direct Cost : ¥3,700,000)
Fiscal Year 1998 : ¥800,000 (Direct Cost : ¥800,000)
Fiscal Year 1997 : ¥2,900,000 (Direct Cost : ¥2,900,000)
To elucidate the patho-physiological role of parathyroid-hormone-related peptide (PTHrP) in liver disease it is essential to investigate on the molecular mechanism of PTHrP receptor mediated signal transduction in hepatic parenchemal cells and non-parenchemal cells including endothelial cells. In the present projects we have initially concentrated the analysis of PTHrP expression in various disease (J Pathol 182 : 174-9, J Pathol 187 : 217-22). Next, we have studied the effect of various fragments of PTHrP in primary culture and function of the cell lines transfected PTHrP.Finally, we have try to develop the PTHrP transgenic animal using tissue specific promoter of the liver, analyze the pathophysiological role of PTHrP in liver regeneration.
The action of exogenously added hPTHrP (1-34), hPTHrP (1-141), hPTHrP (100-114) and hPTH (1-34) on thymidine incorporation, alpha(l) type II collagen gene expression, intracellular cAMP and [Ca^2^+]i level was similar. Antisense oligonucleotides de
creased PTHrP mRNA translation specifically inhibited DNA synthesis. These data are speculated that there is no significant difference among exogenously added hPTH and hPTHrP, on the other hand intracellular PTHrP may have a yet unknown biological role, in addition to a classical PTH/PTHrP receptor-mediated function (J Endocrinol 150 : 359-368).
To further extend the basic research, we have focused on the critical events induced by abnormal expression of cytokines including PTHrP escaping from physiological regeneration or apoptosis, which can eventually induce gene instability and abnormal cell proliferation. The experimental design is in vivo rat animal model, which is subcutaneously implanted with pituitary tumor producing PTHrP.
Surprisingly, these rats arc developed the liver fibrosis and splenoniegaly in 3 months after tumor cell inoculation, and also showed the significantly increased number of GST-P positive focus.
Further studies are now continuing on PTHrP transgenic animal model, which was already, established positive transgene clone.
Finally, we acknowledge a support from this grant and a valuable contribution of our post doe fellows and staffs. Less