OHTSURU Akira Nagasaki University, School of Medicine, Assis., 医学部, 助手 (00233198)
SICHIJO Kazuko Nagasaki University, School of Medicine, Assis., 医学部, 助手 (90136656)
ITO Masahiro Nagasaki University, School of Medicine, Assoc.Prof., 医学部, 助教授 (30184691)
|Budget Amount *help
¥2,100,000 (Direct Cost : ¥2,100,000)
Fiscal Year 1997 : ¥700,000 (Direct Cost : ¥700,000)
Fiscal Year 1996 : ¥1,400,000 (Direct Cost : ¥1,400,000)
To elucidate the patho-physiological role of parathyroid-hormone-related peptide (PTHrP) in vascular system, it is essential to investigate on the molecular mechanism of PTHrP receptor mediated signal transductionin in vascular smooth muscle cells (VSMC) or endotherial cells. In the present projects, we have initially concentrated the analysis of PTHrP expression in various disease involeved with vascular systems. 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 develope the potentially therapeutic approach using antisense PTHrP,based on the pathophysiological role of PTHrP in VSMC.
The restenosis is a major problem after baloon angioplasty. Thus, we examined the expression of PTHrP and its receptor in both rat model and human atherectomy samples. PTHrP is a key cytokine to regulate the cell motility (Arterioscl Thromb Vascul Bio1 16 : 565-575 1996).
The action of exogenously added h
PTHrP (1-34), hPTHrP (1-141), hPTHrP (100-114) and hPTH (1-34) on thymidine incorporation, alpha (1) type II co11agen gene expression, intracellular cAMP and [Ca^<2+>]i level was similar. Antisense oligonucleotides decreased 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 Endocrinology 150 : 359-368 1996).
To further extend the basic research, we have focused on the critical events of cancer by abnormal expression of PTHrP.PTHrP overexpression have been found in various cancers associated with malignant progression without hypercalcemia. The in vivo experimental design which was implanted with PTHrP expresion vector producing cell lines in rat have demanstrated in vivo tumor progression and caltified matrix formation around the cells (Endocrine J 43 : 527-535 1996). Furthermore, the antisense PTHrP oligo-nucleotide therapy have been reported as a anti-angiogenic therapy against PTHrP producing tumor (Cancer Res 56 : 77-86, 1996).
Finally, we acknowledge a support from this grant and a valuable contribution of our post doc fellows and staffs. Less