Sugar chain-related gene and use thereof

Abstract

As a result of dedicated studies, the present inventors succeeded in discovering, for the first time, that fibrogenesis could be suppressed at the physiological tissue level by inhibiting sulfation at position 4 or 6 of GalNAc, which is a sugar that constitutes sugar chains. Furthermore, the present inventors conducted studies using various disease model animals, and as a result, successfully demonstrated that inhibitors of sulfation at position 4 or 6 of GalNAc had therapeutic effects on diseases caused by tissue fibrogenesis (tissue fibrogenic disorders).

1 . A tissue fibrogenesis suppressing-agent, comprising:
 an siRNA that suppresses the expression of the sulfotransferase that transfers a sulfate to position 4 or 6 of the N-acetylgalactosamine.   
     
     
         2 .- 6 . (canceled) 
     
     
         7 . A method of screening for a tissue fibrogenesis suppressing-agent, which comprises the step of selecting a compound that inhibits sulfation at position 4 or 6 of N-acetylgalactosamine that constitutes a sugar chain. 
     
     
         8 . A method of screening for a tissue fibrogenesis suppressing-agent, which comprises the steps of:
 (a) contacting a test compound with N-acetylgalactosamine or a sugar chain comprising N-acetylgalactosamine;   (b) determining the degree of sulfation at position 4 or 6 of N-acetylgalactosamine; and   (c) selecting a compound that reduces the degree of sulfation as compared to when the test compound is not contacted.   
     
     
         9 . A method of screening for a tissue fibrogenesis suppressing-agent, which comprises the steps of:
 (a) contacting a test compound with a sulfotransferase that transfers a sulfate to position 4 or 6 of N-acetylgalactosamine;   (b) determining the sulfotransferase activity of the enzyme; and   (c) selecting a compound that reduces the activity as compared to when the test compound is not contacted.   
     
     
         10 . A method of screening for a tissue fibrogenesis suppressing-agent, which comprises the steps of:
 (a) contacting a test compound with a cell expressing a gene encoding a sulfotransferase that transfers a sulfate to position 4 or 6 of N-acetylgalactosamine;   (b) determining the expression level of the gene in the cell; and   (c) selecting a compound that reduces the expression level of the gene as compared to when the test compound is not contacted.   
     
     
         11 . A method of screening for a tissue fibrogenesis suppressing-agent, which comprises the steps of:
 (a) contacting a test compound with a cell or cell extract containing a DNA wherein a reporter gene is operably linked to the transcriptional regulatory region of the gene encoding a sulfotransferase that transfers a sulfate to position 4 or 6 of N-acetylgalactosamine;   (b) determining the expression level of the reporter gene; and   (c) selecting a compound that reduces the expression level of the reporter gene as compared to when the test compound is not contacted.   
     
     
         12 . A method of producing a pharmaceutical composition for treating or preventing a fibrogenic disorder, which comprises the steps of:
 (a) selecting a tissue fibrogenesis suppressing-agent from test compounds by the method of  claim 11 ; and   (b) combining the agent with a pharmaceutically acceptable carrier.   
     
     
         13 . A method of treating a fibrogenic disorder, comprising:
 identifying a subject as suffering from a fibrogenic disorder of a tissue selected from the group consisting of cardiac tissue, gastrointestinal tissue, lung tissue, pancreatic tissue, kidney tissue, ocular tissue, cranial nerve tissue, and skin tissue;   administering to the subject a therapeutically effective amount of an siRNA that suppresses expression of a gene encoding a sulfotransferase that transfers a sulfate to position 4 or 6 of N-acetylgalactosamine;   wherein the siRNA suppresses expression of a nucleotide sequence selected from the group consisting of a C4ST-1 gene (SEQ ID NO:6), a C4ST-2 gene (SEQ ID NO:8), and a C4ST-3 gene (SEQ ID NO:10).