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Compositions and methods for modulating cells via CD14 and toII-like receptor 4 signaling pathway

A signal transduction and receptor technology, applied in the direction of antibodies, biological testing, pharmaceutical formulations, etc., can solve the problem of not having, no host to distinguish between smooth and rough LPS chemotypes

Inactive Publication Date: 2008-07-23
THE SCRIPPS RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Because lipid A, which has no added sugars at all, is the biologically active part of LPS, the sugar chains are thought to play a supporting role in endotoxicity, and there is no clear evidence that the host differentiates between smooth and rough LPS chemotypes

Method used

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  • Compositions and methods for modulating cells via CD14 and toII-like receptor 4 signaling pathway
  • Compositions and methods for modulating cells via CD14 and toII-like receptor 4 signaling pathway
  • Compositions and methods for modulating cells via CD14 and toII-like receptor 4 signaling pathway

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Experimental program
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Effect test

Embodiment 1

[0340] Heedless mutation transmissible recessive

[0341] Heedless, a transmissible recessive LPS-hyperresponsive phenotype identified in G3 animals, was bred to generate homozygous stock. Mutations occurred to inhibit TNF production in response to the smooth LPS chemotype but not the rough LPS chemotype or lipids from S. minnesota (Fig. 1a-c). The mutation also partially reduced the response to TLR2-TLR6 ligands (Fig. 1d-h), including synthetic diacylated macrophage-activating lipopeptide-2 (MALP-2; stereo isomer reduction > S stereoisomer) and Pam 2 CSK 4 And highly purified lipoteican and zymosan A. to Pam 3 CSK 4 (a TLR2-TLR1 ligand) and responses to other known TLR ligands such as Resiquimod (TLR7), poly IC (TLR3) and CpG (TLR9) were normal (Fig. 1i-l). Thus, this mutation produces a ligand-restricted but essentially complete effect on signaling through TLR4 and a broad but partial effect on signaling through the TLR2-TLR6 complex.

[0342] Figure 1 shows the speci...

Embodiment 2

[0344] Resistance to shock independent of LPS chemotype

[0345] Because Heedless selectively prevents TNF production in response to smooth LPS, the mutation was expected to protect mice only from the lethal effects of smooth (but not rough) LPS. Mutant purified mice or heterozygous C57BL / 6 littermates were injected with 1 mg of LPS (smooth or rough chemotype) by intraperitoneal route. All heterozygous mice receiving rough or smooth LPS died within 36 hours. Contrary to expectations, all homozygous Heedless mice survived whether rough or smooth LPS was administered. All Heedless homozygous mice showed much less sensitivity to rough and smooth chemotypes than controls (Figures 2a and 2b). Although rough LPS can induce TNF production by Heedless macrophages, mutations must disable at least some aspects of the LPS response.

Embodiment 3

[0347] Heedless suppresses LPS-induced type I IFN production

[0348] All forms of LPS signal via the TLR4 to MyD88-independent pathway (involving the aptamers MyD88 and Mal) and the MyD88-independent pathway (involving the aptamers TRIF and TRAM). Poltorak et al., Science 282:2085-2088, 1998; Hoebe et al., Nature 640-643, 2003; Yamamoto et al., Nat. Immunol.4:1144-1150, 2003; Kawai et al., 11(1):115-122, 1999 ; Yamamoto et al., Nature 420:324-329, 2002; Horng et al., Nature 420:329-333, 2002. LPS-induced IFN-β production is entirely dependent on TRIF and TRAM, which allow phosphorylation and dimerization of the IFN-β transcription factor IRF-3. Hoebe et al., Nature 424:743-748, 2003; Yamamoto et al., Science 301:640-643, 2003; Yamamoto et al., Nat. Immunol. 4:1144-1150, 2003. Utilizing the tyrosine kinase Tyk2 and the signal transducer and activator of transcription STAT-1, IFN-β increases its own synthesis via autoamplication loops and is known to play a major role in LPS ...

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Abstract

Compositions and methods for screening and identifying compounds that modulate Toll-like receptor 4 (TLR4) pathway signaling via CD14 and ligands are provided. Provided are methods of treating various disease states, such as inflammatory or autoimmune diseases, in mammalian subjects by modulating Toll-like receptor 4 (TLR4) pathway signaling through CD14 and ligands. Transgenic non-human animals and methods of developing transgenic non-human animals are provided, wherein the transgenic non-human animals contain a loss-of-function mutation in the CD14 gene.

Description

[0001] Statement of Government Funding [0002] This invention was made with government support under Grant No. U54-AI54523 from the National Institutes of Health. The government has certain rights in this invention. [0003] Cross References to Related Applications [0004] This application claims U.S. Provisional Application No. 60 / 678,393, filed May 6, 2005, and U.S. Provisional Application No. 60 / 678,393, filed May 4, 2006, via Express Mail No. EV800285450US, entitled "Combined Modulation of Cells Via CD14 and Toll-like Receptor 4 Signaling Pathways" COMPOSITIONSAND METHODS FOR MODULATING CELLS VIA CD14 AND TOLL-LIKERECEPTOR 4 SIGNALING PATHWAY", both of which are incorporated herein by reference. technical field [0005] The present invention relates generally to molecular immunology and treatment of human disease. The present invention relates to methods for screening and identifying compounds based on properties of the Toll-like receptor 4 (TLR4) pathway that signals...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395A61K39/205G01N33/53
Inventor 布鲁斯·比特勒蒋争凡
Owner THE SCRIPPS RES INST
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