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PAR-1 Activation by Metalloproteinase-1 (MMP-1)

Inactive Publication Date: 2012-05-17
TUFTS MEDICAL CENTER INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0027]In one aspect, the agent reduces the size of atherosclerotic plaque within the aorta of the patient,

Problems solved by technology

Platelet activation and aggregation, while needed for normal physiological functions such as hemostasis, can lead to a myriad of oft-lethal and highly debilitating conditions and pathologies when her regulatory mechanisms malfunction.

Method used

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  • PAR-1 Activation by Metalloproteinase-1 (MMP-1)
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  • PAR-1 Activation by Metalloproteinase-1 (MMP-1)

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Embodiment Construction

[0100]Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art. The following definitions are provided to help interpret the disclosure and claims of this application. In the event a definition in this section is not consistent with definitions elsewhere, the definition set forth in this section will control.

[0101]As used herein, the term “about” or “approximately” when used in conjunction with a number refers to any number within 5, 10 or 15% of the referenced number.

[0102]As used herein the terms “administration”“administering,” or the like, when used in the context of providing a pharmaceutical or nutraceutical composition to a subject generally refers to providing to the subject one or more pharmaceutical compositions comprising the agent, e.g., an angonist or antagonist of the MMP-1 mediated PAR-1 signaling pathway, in combination with an appropriate delivery vehicle by any means such tha...

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Abstract

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.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to and the benefit of co-pending U.S. provisional patent application Ser. Nos. 61 / 168,353 and 61 / 168,360, both of the above title and both filed on Apr. 10, 2009, which applications are incorporated herein by reference in entirety to the extent allowed by applicable laws.STATEMENT REGARDING FEDERALLY FUNDED RESEARCH AND DEVELOPMENT[0002]This invention was made with Government support under Grant Nos. R01 HL-57905, R01 HL-64701, and R01 CA-122992, awarded by the National Institutes of Health. The government has certain rights in this invention.FIELD OF INVENTION[0003]The present invention relates to the diagnosis and treatment of thrombotic conditions including those related to acute coronary syndrome and atherosclerosis. The invention also relates to means of preserving platelets for research or clinical uses.BACKGROUND[0004]Platelet activation and aggregation, while needed for normal physiological functio...

Claims

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Application Information

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IPC IPC(8): A61K38/55C07K7/06A61P7/02C12Q1/37A61K9/00A61K31/443C07K2/00G01N33/566A61K38/08
CPCA61K31/00C07K2317/76A61L17/005A61L27/54A61L29/16A61L31/16A61L2300/42A61L2300/434A61L2300/436A61K31/65A61K38/08A61K38/10A61K39/3955A61K2039/505C07K16/40A61K45/06A61P35/00A61P43/00A61P7/00A61P7/02A61P9/00A61P9/10
Inventor KULIOPULOS, ATHANKOUKOS, GEORGIOS
Owner TUFTS MEDICAL CENTER INC
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