| Project/Area Number |
16390024
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | Kyoritsu University of Pharmacy |
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Principal Investigator |
KASAHARA Tadashi Kyoritsu University of Pharmacy, Professor, 薬学部, 教授 (60049096)
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| Co-Investigator(Kenkyū-buntansha) |
SONODA Yoshiko Kyoritsu University of Pharmacy, Associate Professor, 薬学部, 助教授 (30050743)
YOKOTA Eriko Kyoritsu University of Pharmacy, Instructor, 薬学部, 講師 (10222457)
AGO Megumi Kyoritsu University of Pharmacy, Assistant, 薬学部, 助手 (30445192)
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| Project Period (FY) |
2004 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥10,400,000 (Direct Cost: ¥10,400,000)
Fiscal Year 2006: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2005: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2004: ¥4,400,000 (Direct Cost: ¥4,400,000)
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| Keywords | TNF signaling / TRAF6 / NF-kB / Focal adhesion kinase / DNA microarray / MALDI-TOF / MS / Apoptosis / FAK / FAK過剰発現 |
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| Research Abstract |
Many signaling molecules have been identified which act on the IL-1 and TNFa-mediated signaling. We have studied the role of the focal adhesion kinase (FAK) and TNF receptor-associated factors (TRAF) in the cytokine signaling and apoptosis induced by various apoptosis inducing agents. This system was adopted to develop several assay systems to find new immunomodulatory and anti-inflammatory drugs. Our findings are followings.
1) We found that FAK deficient MEF derived from FAK-/-mice is more susceptible to the TNFa and actinomycin D-induced apoptosis than the FAK+/-cells, indicating the anti-apoptotic role against the cell-death inducing reagents. In this study, FAK was associated with RIP, while RIP was recruited in the DISC in the FAK-/-cells (Takahashi et al. 2007).
2) In addition, TRAF6-/-MEF is more sensitive to the TNFa and actinomycin-D induced cell death. In this system, reactive oxygen species (ROS) was involved in the cell-death and therefore, antioxidant reagent, BHA restored
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ROS-induced cell death. Thus, TRAF6 was involved in the ROS induced apoptosis (Ichikawa et al. 2006).
Above two cell-culture systems are found to be easily applicable to the screening antioxidant reagents which protects from apoptosis-inducing conditions.
3) We found that FAK-overexpressed HL-60 is resistant against apoptosis induced by the various apoptosis-inducing agents including TRAIL. In contrast, FAK-overexpressed HL-60 is reftractory to the ATRA-induced differentiation. This refactoctory condition was resulted from the hyperphosphorylation of Rb protein and subsequent the c/EBPa inactivation (Hashimoto et al. 2006).
4) Glycyrrhizin (GL) and related compounds were found to regulate production of anti-inflammatory chemokines, IL-8 and eotaxin-1 in the human lung fibroblasts. In particularly, 11-deoxo-GL and Hetero-30-OH-GL were effective to inhibit IL-8 and eotaxin-1 (Matsui et al. 2004, 2006). These derivatives are now designed to be studied in in vivo assay.
5) Various proteasome inhibitors were found to act differentially in the induction of eotaxin-1 and eotaxin-3 by the TNF and IL-4 in the human lung fibroblast (Rokudai et al. 2006).
These study was applicable to the screening of the immunomodulatory and anti-inflammatory agents acting on the various signaling molecules. Less
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