| Project/Area Number |
18591057
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Osaka University |
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Principal Investigator |
TADOKORO Seiji Osaka University, Hospital, Resident (80403062)
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| Co-Investigator(Kenkyū-buntansha) |
TOMIYAMA Yoshiaki Osaka Univetsty, Hospital, Associate Professor (80252667)
KANAKURA Yuzuru Osaka Univetsty, Graduate School of Medione, Professor (20177489)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000)
Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | integrin / signal transduction / platelet / cancer / targeted therapy / 活性化シグナル / 抗血小板薬 / 抗腫瘍薬 |
|---|
| Research Abstract |
【Development of new targeted therapy for thrombosis or cancer】
We have reported that talin is required for αIIβ33 activation downstream of a number of physiologically relevant signaling pathways. In this project we chose talin as a new potential target for antiplatelet therapy. Palmitoylated peptides based on the sequence of human 33 were synthesized to block talin-β3 interaction. This peptide inhibited platelet aggregation induced protease-activated receptor 1- activating peptide (PAR1-AP) or PAR4-AP. It also brought about sequence specific dose-dependent inhibition of PAC-1 binding without affecting granular secretion. These inhibitory effects were observed in both washed platelets and platelet rich plasma. These peptides might be an effective tool not only developing drug but also investigating short signaling motifs in molecular signaling pathways.
Molecular mechanism of integrin activation signaling】
Integrin activation is regulated by many different biochemical signaling pathways th
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rough the integrin cytoplasmic tail. The binding of the cytoskeletal proteins to integrin cytoplasmic tails leads to the conformational rearrangements of integrin extracellular domains that modulate their affinity. We proposed a new role for a-actinin in inside-out integrin activation evaluating by the time-dependent changes of activated aIIbβ3. α-Actinin was associated with αIIbβ3 in resting human platelets. Inside-out signaling from PAR dephosphorylated α-actinin and activated αIIbβ3 by changing α-actinin localization. When αIIbβ3 activation signal dwindled, α-actinin came back to αIIbβ3 with rephosphorylated. Overexpressed α-actinin increased its affinity with αIIbβ3 and inhibited PAR induced initial αIIbβ3 activation in human megakaryoblastic CMK cells- Furthermore even as α-actinin dissociated from integrin, the selectively blockade of talin-β3 interaction brought about the inhibition of αIIbβ3 activation. These observations suggest that α-actinin might play a role in setting integrins default low-affinity ligand-binding state in resting platelets and regulate αIIbβ3 activation. Less
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