| Project/Area Number |
10557120
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 展開研究 |
|---|
| Research Field |
Digestive surgery
|
|---|
| Research Institution | KYOTO UNIVERSITY |
|---|
Principal Investigator |
YAMAMOTO Yuzo Kyoto University, Graduate School of Medicine, Lecturer, 医学研究科, 講師 (70281730)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
MORIMOTO Taisuke Kyoto University, Graduate School of Medicine, Lecturer, 医学研究科, 講師 (60135910)
FUKUMOTO Manabu Tohoku University, Institute of Developing, aging and Cancer, Professor, 加齢研究所, 教授 (60156809)
YAMAOKA Yoshio Kyoto University, Graduate School of Medicine, Professor, 医学研究科, 教授 (90089102)
OKETANI Kiyoshi Eisai Co. Ltd. Institute for drug evaluation, Researcher, 薬物評価研究所, 研究員
YAMAMOTO Naritaka Kyoto University, Graduate School of Medicine, Instructor, 医学研究科, 助手 (30253298)
|
|---|
| Project Period (FY) |
1998 – 1999
|
| Project Status |
Completed (Fiscal Year 1999)
|
| Budget Amount *help |
¥9,400,000 (Direct Cost: ¥9,400,000)
Fiscal Year 1999: ¥4,400,000 (Direct Cost: ¥4,400,000)
Fiscal Year 1998: ¥5,000,000 (Direct Cost: ¥5,000,000)
|
|---|
| Keywords | geranylgeranylacetone / heat shock protein / molecular chaperone / preconditioning / ischemia-reperfusion injury / ischemic tolerance / Chaperone inducer / pharmacological modulation / Geranylgeranylacetone / 熱ショック蛋白 / 分子シャペロン / プレコンデショニング / 虚血再潅流障害 / 虚血耐性 / シャペロン誘導剤 / 薬理学的修飾 / GGA誘導体 |
|---|
| Research Abstract |
This study aimed to increase the efficacy of stress response by modulating with drugs. In order to clarify the effective action points of drugs, mechanism of heat shock preconditioning in the acquisition of ischemic tolerance was investigated. As a result, mitochondrial protection during ischemia and protection from protein denaturation upon oxidative stress were proved. In addition, heat shock preconditioning was effective even in the livers with steatosis or fibrosis. Deteriorated hepatic microcirculation in the state of brain death was also improved by heat shock preconditioning.
Two drugs, --Doxorubicin and Geranylgeranylacetone (GGA) -- could modify the stress response. Although we tried also Herbimycin A, Futhan, DCIC, and Sulindac, these drugs had no apparent effects on the preconditioning of the liver. With regard to Doxorubicin, it could induce HSP72 and HSP73 in the liver 48 hours after intravenous systemic administration and produced ischemic tolerance as strong as heat shock preconditioning. Although oral administration of GGA per se did not induce HSPs in the liver, it could decrease the duration of heat shock stress that is necessary to induce HSPs.
As other strategies to increase the heat shock preconditioning effect, repetition of heat shock preconditioning was also effective. In addition, increase of adenosine in the liver tissue was a mechanism of ischemic tolerance after ischemic preconditioning. Adenosine A2 receptor stimulator supplanted the effects of ischemic preconditioning.
|
