B6-hSERPINA1 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 (Glu342Lys), lead to alpha-1 antitrypsin deficiency (AATD), resulting in emphysema and chronic obstructive pulmonary disease (COPD) due to uncontrolled protease activity. Additionally, misfolded AAT accumulation in hepatocytes may cause cirrhosis or hepatocellular carcinoma ^[1-3]. The affected tissues primarily include the liver and lungs, with the former being damaged by protein aggregation and the latter by tissue destruction. This highlights AAT's systemic role in protease regulation and disease pathology.

In mice, the Serpina1 gene cluster is located on chromosome 12, spanning a 230 kb genomic region, and encompasses five liver-specific human SERPINA1 homologous genes, which are arranged in the following order: Serpina1b, Serpina1d, Serpina1a, Serpina1c, and Serpina1e. The B6-hSERPINA1 mouse is a humanized model constructed by replacing the mouse Serpina1 gene cluster (from upstream of mouse Serpina1e to downstream of mouse Serpina1b) with the human SERPINA1 gene (from upstream to downstream of human SERPINA1). Homozygous B6-hSERPINA1 mice are viable and fertile and can be used to study the pathogenic mechanisms of emphysema and chronic obstructive pulmonary disease (COPD), cirrhosis, and hepatocellular carcinoma, as well as to develop related therapeutic approaches.