动物造模,儿童严重心脏病 z-bio 2022-09-07 305

　　Severe childhood restrictive cardiomyopathy is a condition that causes the muscles in the walls of the heart muscle to stiffen, preventing the heart from filling properly with blood. Mutations in a protein called BAG3 are known to cause restrictive cardiomyopathy, muscle weakness, difficulty getting enough oxygen, and damage to multiple peripheral nerves, often significantly shortening the lifespan of patients. So far, there has been no successful model of the disease, making research extremely difficult.

　　However, Japanese and German researchers have now created a mouse model that mimics human pathology, making the disease easier to study. The team's data show that restrictive cardiomyopathy caused by mutations in BAG3 alters the process by which damaged proteins are broken down and removed. This causes the protein to build up in the cells, disrupting the heart muscle.

　　The team was able to express a human version of the mutant BAG3 protein in mouse cardiomyocytes, the cells that make up the heart muscle. "Our mouse model successfully mimics the human disease," said first author Assistant Professor Kenichi Kimura. "These mice developed progressive heart failure and growth retardation soon after birth, and only survived for about five weeks."

　　The team studied heart tissue from mice expressing the mutant human BAG3 protein and found changes in the protein quality control system, which ensures the protein folds correctly while increasing levels of autophagy, a process that clears and recycles damaged cells . BAG3 is involved in the breakdown of proteins damaged by mechanical stress. The mutation that causes restrictive cardiomyopathy involves only a single base change in the DNA, resulting in a leucine amino acid in the mutant BAG3 protein that should have a proline in it.

　　The team found that this resulted in reduced solubility and fluidity of the mutant protein, leading to its accumulation in muscle cells. This can lead to fibrosis, or scarring, and cause the heart muscle to stiffen and lose its ability to fully relax, meaning the heart cannot fill with blood properly. Additionally, in a preliminary study using a technique to knock out and reduce the expression of the mutant protein, the researchers were able to reduce disease symptoms in mouse models.

　　Restrictive cardiomyopathy of childhood is a rare but very serious disease. It is hoped that the knowledge provided by this study, and the establishment of a mouse model of the disease to support further research, will lead to better treatments for children with the disease.