发明名称 |
PAR-1 ACTIVATION BY METALLOPROTEINASE-1 (MMP-1) |
摘要 |
Matrix metalloproteases (MMPs) play many important roles in normal and pathological remodeling processes including atherothrombotic disease, inflammation, angiogenesis and cancer. This invention relates to the activation of protease-activated receptor-1 (PAR-1) by endogenous platelet MMP-1 collagenase on the surface of platelets. Exposure of platelets to fibrillar collagen converts the surface-bound pro-MMP-1 zymogen to active MMP-1, which promotes aggregation through PAR-1, MMP-1 is shown to cleave the PAR-1 extracellular domain at a novel site, which then strongly activates Rho-GTP signaling pathways, cell shape change and motility, and MAPK signaling. Blockade of MMP-PAR 1 suppresses thrombogenesis under arterial flow conditions and inhibited thrombosis in animals. These studies provide a link between matrix-dependent activation of metalloproteases and platelet-G protein signaling and identify MMP- 1/PAR-1 as a new target for the treatment and prevention of arterial thrombosis and other thrombotic diseases. |
申请公布号 |
EP3061460(A1) |
申请公布日期 |
2016.08.31 |
申请号 |
EP20150178959 |
申请日期 |
2010.04.12 |
申请人 |
TUFTS MEDICAL CENTER, INC. |
发明人 |
KULIOPULOS, ATHAN;KOUKOS, GEORGIOS |
分类号 |
A61K38/16;A61K9/00;A61P7/00 |
主分类号 |
A61K38/16 |
代理机构 |
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代理人 |
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主权项 |
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地址 |
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