Establishing method and application of dilated cardiomyopathy and zebrafish disease model

A dilated cardiomyopathy and zebrafish technology, applied in the field of medicine, can solve the problem of inability to simulate the characterization of congenital myocardial muscle strength defect cardiomyopathy

Active Publication Date: 2015-01-14
SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although there are some mouse models for heart failure research in the world, they mainly focus on the regulation of beta-adrenergic receptor activity, and cannot simulate the characterization of congenital myocardial muscle strength defects, a major cardiomyopathy

Method used

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  • Establishing method and application of dilated cardiomyopathy and zebrafish disease model
  • Establishing method and application of dilated cardiomyopathy and zebrafish disease model
  • Establishing method and application of dilated cardiomyopathy and zebrafish disease model

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Experimental program
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Embodiment 1

[0060] Embodiment 1. Determination of detection indicators for screening

[0061] The present invention prepares a zebrafish mutant strain similar to human dilated cardiomyopathy, that is, a titin gene mutant strain, and confirms that the defect is ttn protein truncated function loss ( figure 1 A-B). Titin mutant heterozygotes can be purchased from the Sanger Institute. A pair of titin mutant heterozygous male and female adult fish will produce 100 DCM offspring within a week (a pair of fish will produce 400 embryos in a week, and 25% of the offspring will be affected).

[0062] Through the identification of sequencing technology, it was confirmed that there was a base change of TAT-TAA in the N2B domain of the titina gene, which produced a stop codon, which made the translation of titina protein prematurely terminated. The mutation type of this mutant strain was a truncated titin mutation. The morphological phenotype of the mutant strain was enlarged pericardium, decreased ...

Embodiment 2

[0068] Embodiment 2, drug screening method

[0069] The method for screening small molecular compounds for the treatment of DCM provided by the present invention adopts the model organism sarcomere-deficient zebrafish, and the specific steps are as follows:

[0070] 1. Selection and preparation of drug screening library

[0071] The compounds used for screening include 640 small molecule drugs that have been approved by the FDA for clinical use, 1,057 small molecule inhibitor libraries from Tocris, and 1,200 compound libraries with structural and activity diversity from Prestwick. Each small molecule compound was prepared as a 0.5mM stock solution in DMSO as the solvent. The concentration selected in the compound library of this example is 5 μM as the initial screening concentration, and the secondary screening uses a concentration gradient of 2-25 μM.

[0072] 2. embryo preparation

[0073] Of the offspring produced by the mating of heterozygotes (titin+ / -) with TTN muta...

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Abstract

The invention relates to an establishing method and application of a dilated cardiomyopathy and zebrafish disease model. A disease model simulating human congenital dilated cardiomyopathy (CDCM) is firstly established; and the disease model can be used as a drug screening model to be applied to screening of drugs capable of relieving symptoms of heart failure caused by CDCM. The method provided by the invention is an economic and rapid high-content screening method; and the obtained compound has relatively high specificity and druggability.

Description

technical field [0001] The invention belongs to the technical field of medicine, and more specifically, the invention relates to the establishment and application of a zebrafish model of sarcomere defect-induced dilated cardiomyopathy. Background technique [0002] Dilated congenital cardiomyopathy (Congenital Dilated Cardiomyopathy, CDCM) is a major type of congenital cardiomyopathy, clinically manifested as left ventricle or bilateral ventricle dilation, accompanied by a decrease in positive muscle strength. Children's prognosis is 80% fatal within five years, and survivors may suffer from sequelae or require heart transplantation. The penetrance rate of DCM caused by congenital gene variation in adults reaches 95% after the age of 40, and the mortality rate is still high (average survival time after onset is 1.7 years for males and 3.2 years for females). And the syndrome also ranks first. [0003] Cardiomyocyte sarcomere defects are one of the main causes of CDCM. Tit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/519A61K38/00A61P9/04
CPCA61K31/519A61K31/522
Inventor 周勇高磊邓敏陈漪
Owner SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI
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