Serpina1(a-e) KO Mice

Catalog Number: I001121

Strain Name: C57BL/6JCya-Serpina1a&Serpina1b&Serpina1c&Serpina1d&Serpina1eem1/Cya

Genetic Background: C57BL/6JCya

 

Strain Description

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.

Serpina1(a-e) KO mice are gene knockout (KO) models created by gene editing technology to knock out the protein-coding sequences of the Serpina1(a-e) genes (homologous to the human SERPINA1 gene) in mice. Preliminary data indicate almost no expression of the Serpina1 gene in the liver of these mice, with no significant pulmonary abnormalities observed at 8 weeks of age. Serpina1(a-e) KO mice 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.

Strain Strategy

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. This strain was generated using gene editing technology to specifically knock out the gene sequence spanning from exon 5 of the mouse Serpina1b gene to exon 1 of the Serpina1e gene.

 

Application

  • Pathogenesis research and therapeutic drug evaluation for emphysema and chronic obstructive pulmonary disease (COPD);
  • Pathogenesis research and therapeutic drug evaluation for liver cirrhosis or hepatocellular carcinoma.

 

Validation data

1. RT-qPCR Detection

Figure 1. RT-qPCR analysis of liver gene expression in 8-week-old homozygous Serpina1(a-e) KO and wild-type (WT) mice (n♂=2, n♀=2). The results indicate that Serpina1 gene expression is nearly absent in the liver of Serpina1(a-e) KO mice compared to WT mice*.

*Note: The mouse Serpina1(a-e) genes are highly homologous, and one pair of primers can be used to detect the expression loss of all five genes.

 

2. H&E Staining

Figure 2. Pulmonary pathology observation by H&E staining in 8-week-old female homozygous Serpina1(a-e) KO and wild-type (WT) mice. The results show that no destruction of alveolar walls and lung parenchyma was observed in 8-week-old Serpina1(a-e) KO mice compared to WT mice.

 

References
[1]Stoller, J. K., & Aboussouan, L. S. (2012). Alpha1-antitrypsin deficiency. The Lancet, 365(9478), 2225-2236.
[2]Greene CM, McElvaney NG. Z α-1 antitrypsin deficiency and the endoplasmic reticulum stress response. World J Gastrointest Pharmacol Ther. 2010 Oct 6;1(5):94-101.
[3]Lomas DA, Mahadeva R. Alpha1-antitrypsin polymerization and the serpinopathies: pathobiology and prospects for therapy. J Clin Invest. 2002 Dec;110(11):1585-90.