TG-hSERPINA1*E366K Mouse

The SERPINA1 gene encodes alpha-1 antitrypsin (AAT), a serine protease inhibitor primarily synthesized and secreted by hepatocytes in the liver, with additional expression in immune cells such as macrophages. AAT's main function is to inhibit neutrophil-derived proteases (e.g., elastase) to protect lung tissue from enzymatic degradation. This glycoprotein is crucial for maintaining lung tissue elasticity and regulating inflammatory responses. Mutations in the Serpina1 gene, particularly the Z variant (such as the most common mutation p.E366K), can cause alpha-1 antitrypsin deficiency (AATD), which in turn leads to emphysema and chronic obstructive pulmonary disease (COPD). The pathological mechanism of these diseases stems from dysregulated protease activity. Additionally, the intracellular accumulation of misfolded AAT in hepatocytes may also induce cirrhosis or hepatocellular carcinoma ^[1-3]. Individuals carrying the ZZ genotype face the highest risk of developing pulmonary and hepatic disease manifestations: in the liver, protein aggregation causes cellular damage; in the lungs, tissue destruction triggers disease ^[4]. This highlights AAT's systemic role in protease regulation and disease pathology.

The TG-hSERPINA1*E366K mouse is generated by integrating the Human SERPINA1 Genomic DNA (the region from ~5kb upstream of exon 1 to ~3kb downstream of exon 5) into the mouse genome via transgenesis (TG) technology. A p.E366K (GAG to AAG) point mutation is introduced into exon 5 of this integrated human SERPINA1 sequence. This model can be used to study diseases such as alpha-1 antitrypsin deficiency (AATD), emphysema, chronic obstructive pulmonary disease (COPD), cirrhosis, and hepatocellular carcinoma, as well as to develop relevant therapeutic strategies.