Compositions and methods for modulating collagen and smooth muscle actin expression by serpine2

An actin, smooth muscle technology, applied in chemical instruments and methods, drug combinations, immunoglobulins, etc., can solve problems such as no drug therapy

Inactive Publication Date: 2011-12-21
五佳医疗股份有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, idiopathic pulmonary fibrosis is a chronic, progressive, and often fatal interstitial lung disease for which there is no proven drug therapy

Method used

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  • Compositions and methods for modulating collagen and smooth muscle actin expression by serpine2
  • Compositions and methods for modulating collagen and smooth muscle actin expression by serpine2
  • Compositions and methods for modulating collagen and smooth muscle actin expression by serpine2

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0201] Example 1: Effect of purified SERPINE2 protein on RNA expression

[0202] The effect of SERPINE2 on lung fibroblasts was assessed by incubating normal human lung fibroblasts (NHLF) in fibroblast growth medium. Harvest NHLF cells. Cells were then pelleted, resuspended in growth medium, dispensed at 200ul per well at 8000 cells per well, and incubated at 37°C, 5% CO 2 Incubate for 6 hours. 6 hours after dispensing, cells were serum starved by removing complete growth medium and adding 200 ul starvation medium (Clonetics Fibroblast Basal Medium (FBM) (Lonza Cat. #CC-3131 ) + 0.5% BSA fraction to cells V) and at 37°C, 5% CO 2 Incubate for 16-24 hours.

[0203] Starvation medium was removed from the cells and 75ul of co-treatment was added immediately followed by 75ul of protein treatment. Co-treatments were starvation medium and TGF-β1 or IL-13 added at one of three doses, TGF-low treatment was 0.1 ng / ml TGF-β1 (final concentration in the experiment was 0.05 ng / ml); TG...

Embodiment 2

[0206] Example 2: Generation of constructs expressing wild-type SERPINE2

[0207] Constructs containing the nucleotide sequence of wild-type SERPINE2 DNA and expressing wild-type SERPINE2 protein were generated.

[0208] The nucleotide sequence of wild-type SERPINE2 DNA is:

[0209] atgaactggcatctccccctcttcctcttggcctctgtgacgctgccttccatctgctcccactt

[0210] caatcctctgtctctcgaggaactaggctccaacacggggatccaggttttcaatcagattgtga

[0211] agtcgaggcctcatgacaacatcgtgatctctccccatgggattgcgtcggtcctggggatgctt

[0212] cagctgggggcggacggcaggaccaagaagcagctcgccatggtgatgagatacggcgtaaatgg

[0213] agttggtaaaatattaaagaagatcaacaaggccatcgtctccaagaagaataaagacattgtga

[0214] cagtggctaacgccgtgtttgttaagaatgcctctgaaattgaagtgccttttgttacaaggaac

[0215] aaagatgtgttccagtgtgaggtccggaatgtgaactttgaggatccagcctctgcctgtgattc

[0216] catcaatgcatgggttaaaaacgaaaccagggatatgattgacaatctgctgtccccagatctta

[0217] ttgatggtgtgctcaccagactggtcctcgtcaacgcagtgtatttcaagggtctgtggaaatca

[0218] cggttccaacccgagaacacaaagaa...

Embodiment 3

[0236] Example 3: Generation of SERPINE2 muteins that do not bind LRP

[0237] A construct containing the nucleotide sequence of a SERPINE2 mutein that is unable to bind low-density lipoprotein receptor-related protein (LRP) was generated. This mutein contains the following mutations at amino acid positions 48 and 49 of SERPINE2: H48A and D49E.

[0238] The DNA nucleotide sequence of the LRP-binding mutein of SERPINE2 is:

[0239] atgaactggcatctccccctcttcctcttggcctctgtgacgctgccttccatctgctcc

[0240] cacttcaatcctctgtctctcgaggaactaggctccaacacggggatccaggttttcaat

[0241] cagattgtgaagtcgaggcctgcagaaaacatcgtgatctctccccatgggattgcgtcg

[0242] gtcctggggatgcttcagctgggggcggacggcaggaccaagaagcagctcgccatggtg

[0243] atgagatacggcgtaaatggagttggtaaaatattaaagaagatcaacaaggccatcgtc

[0244] tccaagaagaataaagacattgtgacagtggctaacgccgtgtttgttaagaatgcctct

[0245] gaaattgaagtgccttttgttacaaggaacaaagatgtgttccagtgtgaggtccggaat

[0246] gtgaactttgaggatccagcctctgcctgtgattccatcaatgcatgggttaaaaacga...

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Abstract

The invention encompasses methods and compositions for increasing or decreasing collagen 1A1 expression and / or α-smooth muscle actin expression in lung fibroblasts using SERPINE2 and antagonists of SERPINE2. The invention also encompasses methods and compositions for increasing or decreasing the formation of myofibroblasts. The invention further provides methods and compositions for treatment of lung diseases, such as idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease.

Description

Background of the invention [0001] There are many different types of lung diseases involving pulmonary fibrosis, such as idiopathic pulmonary fibrosis (IPF), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), asthma, and chronic obstructive pulmonary disease (chronic obstructive pulmonary disease). obstructive pulmonary disease, COPD). Howell et al., Am. J. Path. 159:1383-1395 (2001), U.S. Patent Publ. No. 2009 / 0136500 A1. [0002] For example, idiopathic pulmonary fibrosis (IPF) is a common form of interstitial lung disease characterized by fibroblast proliferation and excessive collagen deposition. Hardie et al., Am. J. of Respir. Cell Mol. Biol. 327:309-321 (2007). IPF may arise from a chronic inflammatory process that initiates the focal accumulation of extracellular matrix in the interstitium. Alternatively, IPF may result from lung epithelial injury, which can lead to abnormal wound healing and excessive extracellular matrix formation. To date, ther...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/57C07K14/81
CPCC07K14/811C07K16/38A61K38/57C07K2317/76A61P11/00A61P21/00A61P43/00
Inventor A.布拉斯K.沙利文J.芬纳E.博希K.博伊尔B.旺格K.皮尔斯K.巴维A.达斯F.法雷尔P.西瓦库马
Owner 五佳医疗股份有限公司
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