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Endotoxin-nonresponsive model animal achieved

Foreign code F110003800
File No. E07202US
Posted date Jul 5, 2011
Country United States of America
Application number 57321204
Gazette No. 20070143869
Gazette No. 7557258
Date of filing Sep 29, 2004
Gazette Date Jun 21, 2007
Gazette Date Jul 7, 2009
International application number JP2004014220
International publication number WO2005030269
Date of international filing Sep 29, 2004
Date of international publication Apr 7, 2005
Priority data
  • P2003-338013 (Sep 29, 2003) JP
  • 2004WO-JP14220 (Sep 29, 2004) WO
Title Endotoxin-nonresponsive model animal achieved
Abstract (US7557258)
The present invention is to provide a non-human animal model non-responsive especially to endotoxin being a Gram-negative bacteria cell wall fraction, which is useful to elucidate the function of TIR domain-containing TRIF-related adaptor molecule (TRAM); and a method for screening substances promoting or suppressing responses to ligands recognized by TLR4 with the use of the non-human animal model non-responsive to endotoxin; and the like.
Mice non-responsive to the endotoxin wherein a part or a whole of Tram genes on their chromosome are deleted, the function to express TRAM which is expressed in wild-types is lacked, and the responsiveness to ligands recognized by TLR4 is specifically impaired; is used for screening substances promoting or suppressing responses to ligands recognized by TLR4.
Scope of claims [claim1]
1. A transgenic homozygous TRAM-knock out mouse non-responsive to endotoxin wherein a part or a whole of TRIF-related adaptor molecule (TRAM) genes on its chromosome is deleted, a function of expressing TRAM which is expressed in a wild-type is lacked, and responsiveness to a ligand recognized by TLR4 is specifically impaired.
[claim2]
2. The transgenic homozygous TRAM-knock out mouse non-responsive to endotoxin according to claim 1, which is responsive to PGN, R-848 and CpG ODN, and non-responsive to LPS.
[claim3]
3. A method for screening a substance promoting a response to a ligand recognized by TLR4, wherein a test substance is administered to an immunocyte derived from the knock out mouse of claim 1 or 2 and to an immunocyte derived from a wild-type mouse, and wherein the following responses (a) to (c) to the ligand recognized by TLR4 are measured: (a) cytokine (TNFalpha , IL-6 and IL-12p40) production of macrophage;
(b) splenocyte proliferation, and up-regulation of surface molecules; and
(c) expression of signaling molecules inducing IFN-beta production;
wherein a response for one or more of (a), (b), or (c) in the immunocyte derived from said wild-type mouse but not in the immunocyte derived from said knock out mouse indicates that the test substance promotes a response to a ligand recognized by TLR4.
[claim4]
4. A method for screening a substance promoting a response to a ligand recognized by TLR4, wherein a test substance is administered to the knock out mouse of claim 1 or 2 and to a wild-type mouse, and wherein the following responses (a) to (c) to the ligand recognized by TLR4 are measured: (a) cytokine (TNFalpha , IL-6 and IL-12p40) production of macrophage;
(b) splenocyte proliferation, and up-regulation of surface molecules; and
(c) expression of signaling molecules inducing IFN-beta production;
wherein a response for one or more of (a), (b), or (c) in said wild-type mouse but not in said knock out mouse indicates that the test substance promotes a response to a ligand recognized by TLR4.
[claim5]
5. An immunocyte from the transgenic homozygous TRAM-knock out mouse non-responsive to endotoxin according to claim 1 or 2.
  • Inventor, and Inventor/Applicant
  • AKIRA SHIZUO
  • YAMAMOTO MASAHIRO
  • JAPAN SCIENCE AND TECHNOLOGY AGENCY
IPC(International Patent Classification)
Reference ( R and D project ) ERATO AKIRA Innate Immunity AREA
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