动物实验,先天性再生障碍性贫血 z-bo 2020-09-28 349

　　Normal ribosome biosynthesis is essential for cell survival, proliferation and function. Ribosome biosynthesis dysfunction is related to diamond black obsessive anemia (DBA), 5q syndrome (related to many diseases (such as 5qminus (del (5q)) syndrome)), congenital keratosis (congenital angle) Chemosis) and Bowen-Conradi syndrome. All these diseases are collectively referred to as ribosomal pathology (ribosomal diseases) because they all contain genetic mutations that affect ribosomal biosynthesis and have some of the same clinical characteristics. Spinal hematopoiesis is an evolutionarily conserved and highly regulated process that involves the differentiation of hematopoietic stem cells (HSC) into blood cells of various lineages. Zebrafish is a powerful model for studying the genetics and development of the vertebrate circulatory system, especially in the study of hematopoietic function.

　　The hematopoietic function of zebrafish is highly conserved in mammals. The hematopoietic system is located in a structure called AGM in the dorsal aorta of the zebrafish abdominal wall 28 hours after fertilization. Two days after fertilization, AGM-driven hematopoietic stem cells were transplanted into the tail hematopoietic tissue (CHT), an embryonic structure similar to the liver of a mammalian fetus. The researchers used gene mapping, molecular cloning and other methods to characterize the zebrafish variant cas002, and the new link between ribosome dysfunction and hyperautophagy in regulating HSPC. Revealed. cas002 carries the recessive lethal mutation gene kri11, which plays a role in the key component of small subunit processing encoding rRNA.

　　They confirmed that Kri111 is a necessary condition for normal ribosome biosynthesis, HSPC amplification and phylogeny. Through in vivo imaging and biochemical studies, they found that lack of Kri11 may lead to the accumulation of misfolded proteins in HSPC and excessive PERK activation-dependent autophagy. Treatment with autophagy inhibitors (3-MA and BafA1) or PERK inhibitors (GSK2656157), or inhibition of beclin1 or perk, can significantly restore HSPC proliferation and hematopoietic cell differentiation.