动物造模,儿童严重心脏病新型 z-bio 2021-07-28 275

　　Severe childhood restrictive cardiomyopathy is a condition in which the muscles of the myocardial wall become stiff and prevent the heart from filling blood normally. It is well known that mutations in a protein called BAG3 can cause restrictive cardiomyopathy, weakness, difficulty in getting enough oxygen, and damage to multiple peripheral nerves, which often significantly shorten the lifespan of patients. I have got. So far, there is no successful model of this disease, so it is very difficult to study.

　　However, researchers in Japan and Germany are now creating mouse models that mimic human pathology to facilitate research on this disease. The team's data showed that restrictive cardiomyopathy caused by mutations in BAG3 changed the process of breakdown and removal of damaged proteins. This can cause proteins to accumulate in the cells and interfere with the heart muscle.

　　The  team was able to express the human version of the mutant BAG3 protein in mouse cardiomyocytes (cells that make up the heart muscle). "Our mouse model mimics human diseases very well," said lead author Kenichi Kimura. "These mice developed more severe heart failure and growth retardation shortly after birth, and only survived for about 5 weeks."

　　The  team discovered that the heart of mice expresses a mutated human BAG3 protein. I researched the organization and found changes. The protein quality management system ensures that the protein is folded correctly while increasing the level of autophagy, the process of removing and circulating damaged cells. BAG3 is involved in the breakdown of proteins damaged by mechanical stress. The mutation that causes restrictive cardiomyopathy involves only one base change in the DNA, causing mutations in the leucine amino acid in the BAG3 protein, which should contain proline.

　　The  research team found that this reduces the solubility and fluidity of the mutant protein and accumulates in muscle cells. This can lead to fibrosis and scar formation, which can cause the heart muscle to harden and lose its ability to relax completely. This means that the heart is usually no longer full of blood. In addition, in a preliminary study using technology to knock out and reduce mutant protein expression, researchers were able to reduce disease symptoms in mouse models.

　　Pediatric restrictive cardiomyopathy is a rare but very serious disease. It is hoped that the knowledge provided by this study and the establishment of mouse models of the disease can support further research and provide better treatment for children suffering from the disease.