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A method of increasing GIPCR signalization in the cells of a scoliotic subject

A technology of signal transduction and scoliosis, applied in chemical instruments and methods, biochemical equipment and methods, medical preparations containing active ingredients, etc.

Inactive Publication Date: 2016-03-02
CHU SAINTE JUSTINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] A major limitation in the development of diagnostic tests that can aid in treatment selection for patients is the heterogeneous nature of AIS

Method used

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  • A method of increasing GIPCR signalization in the cells of a scoliotic subject
  • A method of increasing GIPCR signalization in the cells of a scoliotic subject
  • A method of increasing GIPCR signalization in the cells of a scoliotic subject

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0151] Materials and methods

[0152] experimental animal model

[0153] The Review Committee for the Care and Handling of Animals Used in the Study (CHUSainte-Justine) has approved the protocol according to the guidelines of the Canadian Council of Animal Care.

[0154] Breeding pairs of C57Bl / 6j mice without OPN (OPN-deficient mice) or CD44 (CD44-deficient mice) were obtained from Dr. Susan Rittling (Rutger University, NJ, USA) and backcrossed over 10 generations in the C57Bl / 6j background To establish our own colony, and C57Bl / 6j mice were used as wild-type control mice (Charles-River, Wilmington, MA, USA). The C57Bl6 / 6j mouse strain was used because it is naturally deficient in melatonin (VonGall et al., 2000) and exhibits high circulating OPN levels (Aherrahrou et al., 2004). These mice develop scoliosis when they are maintained in the bipedal stage. (Machida et al., 2006). Bipedal surgery was performed after weaning (5 weeks postnatal) by amputation of the forelimb...

Embodiment 2

[0183] Genetic deletion of OPN protects bipedal C57Bl / 6 from scoliosis

[0184] The bipedal C57Bl / 6 mouse is widely used as an animal model to study the pathophysiological events leading to idiopathic scoliosis. These mice rapidly developed spinal deformities after 40 weeks of bipedal walking (Oyama et al., 2006). To determine whether OPN is involved in the development of idiopathic scoliosis, female wild-type (WT) and OPN knockout (OPN - / - ) C57B1 / 6 mice were amputated at 1 month of age forelimbs and tail and subjected to bipedal walking for 36 weeks to induce scoliosis. Representative radiographs of the spine taken at the end of the experimental period at figure 1 shown in A-1D. As expected, scoliosis was not observed in WT or OPN - / - develop in any of the four-legged mice. However, lateral curvature was evident in all bipedal WT mice. Curved convexity is pointing to either side, with no consistent bias. In contrast, analysis of radiographs did not yield bipedal OPN ...

Embodiment 3

[0187] OPN deficiency improves Gi protein-mediated receptor signaling

[0188] We next determined whether OPN deficiency could affect Gi protein-mediated signaling. For this purpose, will be from WT and OPN - / - Osteoblasts from mice were screened for their activation of opioid, somatostatin, α2-adrenoceptor and APJ receptors in response to DAMGO, somatostatin, oxymetazoline and apalene, respectively. These receptors are known to mediate signal transduction through the Gi protein. figure 1 The results shown in F-1I showed that all four compounds elicited - / - Concentration-dependent increase in response in mouse osteoblasts. However, in each case the magnitude of the response was within the OPN - / - greater in osteoblasts than in WT osteoblasts, suggesting that the activation of Gi proteins in OPN - / - promoted in osteoblasts. Furthermore, although response magnitudes were significantly higher in OPN from quadruped and biped - / - Osteoblasts in mice were similar, but signifi...

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Abstract

There is provided a method of increasing GIPCR signalization in the cells of a subject in need thereof comprising administering to the subject an effective amount of an inhibitor of integrin alpha5betal expression and / or activity, whereby GiPCR signalization is increased in the cells of the subject. An inhibitor of integrin alph5betal may be, for example, an agent that inhibits the interaction between f osteopontin (OPN) and integrin alpha5betal. Also provided are methods of determining the risk of developing a scoliosis and based on the presence of at least one copy of a CD44 risk allele and methods of stratifying a subject having a scoliosis and kits for performing these methods. In particular, the method of determining risk identifies SNP rsl467558; an isoleucine to threonine mutation at position 230 of CD44.

Description

[0001] Cross References to Related Applications [0002] This application is PCT application serial number PCT / CA2014 / * filed on June 17, 2014 and published in English pursuant to Article 21(2) of the PCT Treaty, and this application claims the serial number of the U.S. provisional application filed on June 17, 2013 Interest in No. 61 / 835,926. All of the above documents are incorporated herein by reference in their entirety. [0003] Statement Regarding Federally Sponsored Research or Development [0004] Not applicable. field of invention [0005] The present invention relates to a method of increasing GiPCR signaling in cells of a scoliotic subject. [0006] References to Sequence Listings [0007] Pursuant to 37 C.F.R.1.821(c), the Sequence Listing is hereby filed as an ASCII compatible text file named 14033_121_ST25.txt, which was created on June 17, 2014 and has a size of 49 kilobytes. The contents of the aforementioned documents are hereby incorporated by reference ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395A61K31/713A61P19/08C07H21/00C12Q1/68G01N33/48G01N33/53
CPCA61K31/713A61P19/08C07K16/24C07K16/2839C07K16/2884C07K2317/76C12Q1/6883C12Q2600/156G01N33/74G01N2333/70585G01N2800/10A61K39/3955C12Q2600/118C12Q2600/172G01N2800/50
Inventor A·莫罗M-Y·阿库姆 东
Owner CHU SAINTE JUSTINE
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