Method and kit for detecting proliferative diseases causing sclerosis, preventive and/or remedy for proliferative diseases causing sclerosis and method and kit for identifying substance efficacious in

A proliferative disease, detection method technology, applied in chemical instruments and methods, biochemical equipment and methods, medical preparations containing active ingredients, etc., can solve problems such as unclear mechanisms of inhibiting glomerulosclerosis lesions

Active Publication Date: 2006-11-29
HUBIT GENOMIX +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In the glomerulonephritis model of rats, both the proliferation of glomerular mesangial cells and glomerulosclerosis were significantly restored after administration of a neutralizing antibody against PDGF (Non-Patent Document 17 (A7)), but almost Mechanism by which inhibition of cell proliferation suppresses glomerulosclerotic lesions is unclear

Method used

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  • Method and kit for detecting proliferative diseases causing sclerosis, preventive and/or remedy for proliferative diseases causing sclerosis and method and kit for identifying substance efficacious in
  • Method and kit for detecting proliferative diseases causing sclerosis, preventive and/or remedy for proliferative diseases causing sclerosis and method and kit for identifying substance efficacious in
  • Method and kit for detecting proliferative diseases causing sclerosis, preventive and/or remedy for proliferative diseases causing sclerosis and method and kit for identifying substance efficacious in

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Experimental program
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Embodiment 1

[0171] To identify proteins that bind to the CIV site in the promoter region of the mouse Col4 gene, a cDNA library was constructed from glomerular mesangial cells of AGEs-treated mice. In this experiment, a clone encoding a specific transcription factor was selected from a library using the Yeast one-hybrid system, and the clone encoding Smad1 was identified. To confirm the binding of Smad1 to the Col4 promoter region in vivo, chromatin immunoprecipitation (ChIP) was performed. The precipitated DNA was purified, and the promoter region of Col4 was detected by PCR. Anti-Sma1 antibody precipitated chromatin containing CIV-1 sites from cells treated with AGEs ( figure 1 A). Does not precipitate in cells that have been treated with BSA. Smad4 was found to additionally bind to CIV-1 sites ( figure 1 A). Next, the transcriptional activity of Col4 was studied using a reporter assay. A vector was prepared in which the CIV-1 promoter was linked before LacZ, and it was simultaneo...

Embodiment 2

[0206] Glomerulosclerosis is characterized by an increased amount of extracellular matrix (ECM). Collagen type IV (Col4) is one of the main constituents of the increased ECM in glomerular diseases, but the molecular mechanism of transcriptional regulation of the Col4 gene was not clear until the recent report by the present inventors et al. The present inventors revealed that in diabetic nephropathy, Smad1 regulates the overexpression of Col4 at the transcriptional level (A8). Smad1 signals directly to downstream target genes. For example, intrinsically important in osteopontin (A9), inhibition of differentiation (A10), type I collagen (A11), and even in the progression of renal disease (A12). These findings indicate that Smad1 is a transcription factor that is important for the progression of glomerulosclerosis.

[0207] Signal transducer and activator (STAT) proteins are involved in the signaling of many cytokines and proliferation factors. Activation of STAT3 is a key co...

Embodiment 3

[0259] Urine samples were collected from 5 patients with diabetic nephropathy, 1 patient with diabetic nephritis accompanied by sclerosing lesions, 2 patients with diabetic nephritis without sclerosing lesions, and 2 normal subjects, and performed SDS-polyacrylamide electrophoresis, transfer onto the nitrocellulose membrane. Western blotting was performed using anti-Smad-1 antibody (Santa Cruz Biotechnology) and anti-ALK-1 antibody (R&S systems, Minneapolis, USA) as the primary antibody, using the Weatern Blue Kit (Invitrogen, Tokyo, Japan).

[0260] Urine samples were collected from patients hospitalized for diabetic nephropathy before the start of treatment, and then weekly after the start of treatment, and Western blotting was similarly performed using anti-ALK-1 antibody as the primary antibody.

[0261] Smad-1 and ALK-3 were detected in the urine of patients with diabetic nephropathy and sclerosis already visible in the kidney, but not in the urine of normal individuals a...

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Abstract

A method of detecting proliferative diseases causing sclerosis which comprises measuring the expression of at least one substance selected from the group consisting of STAT3, phosphorylated STAT3, Smad1, phosphorylated Smad1, activin receptor-like kinase 1, activin receptor-like kinase 3 and bone morphogenetic protein in a biological sample; a kit therefor; a preventive and / or a remedy for proliferative diseases causing sclerosis which contains, as the active ingredient, a substance having an effect of inhibiting the expression of at least one substance selected from the group consisting of STAT3, phosphorylated STAT3, Smad1 and phosphorylated Smad1; a method of identifying a substance efficacious in preventing and / or treating proliferative diseases causing sclerosis which comprises judging whether or not a test substnace inhibits the expression of at least one substance selected from the group consisting of STAT3, phosphorylated STAT3, Smad1 and phosphorylated Smad1; and a kit therefor.

Description

technical field [0001] The present invention relates to detection methods and kits for proliferative diseases that cause cirrhosis, drugs for the prevention and / or treatment of proliferative diseases that cause cirrhosis, and substances effective in the prevention and / or treatment of proliferative diseases that cause cirrhosis Identification methods and kits. Background technique [0002] α1IV collagen (Col4) is the main component of the vascular basement membrane between the vascular endothelial cells and medial smooth muscle cells, and overproduction of Col4 plays a decisive role in diabetic vascular damage, arteriosclerosis, and aging-related diseases effect. In addition, a persistent hyperglycemia state is considered to be a major cause of complications of diabetes (Non-Patent Documents 1 and 2). Excessive advanced glycation end products (Advanced glycation end products: AGEs) are known to induce various events in blood vessels and other cells through the existence of ...

Claims

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Application Information

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IPC IPC(8): C12N15/00C12Q1/68A61K45/00A61P13/12A61P43/00A61K45/06
CPCG01N2333/71G01N2333/4706C12Q2600/158G01N2333/51A61K45/06C12Q1/6883G01N2333/4703A61P1/16A61P13/12A61P3/10A61P35/00A61P43/00A61P9/00A61P9/10A61P9/12G01N33/48G01N33/53C07K16/2863C07K2317/76C12Q2600/106G01N33/6893
Inventor 土井俊夫安部秀齐
Owner HUBIT GENOMIX
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