PiZ Transgenic Mice

Title:

PiZ transgenic mouse

Category:

Research Tool

NCS:

Inventor: Jeffrey H. Teckman

Summary:

Alpha-1-antitrypsin (a1AT) deficiency is caused by homozygosity for the a1AT mutant Z
gene and occurs in 1 in 2000 births. The Z mutation confers an abnormal conformation on
the protein, resulting in an accumulation within the endoplasmic reticulum of hepatocytes
rather than appropriate secretion. The accumulation of the mutant protein is strikingly
heterogeneous within the liver. Homozygous ZZ children and adults have an increased risk of
chronic liver disease, which is thought to result from this variable intracellular accumulation
of the a1AT mutant Z protein. A well-characterized in vivo model of a1AT mutant Z liver
injury, the PiZ mouse, is useful to better understand the pathways involved in this disease.
The results of the referenced study show an increase in the stimulation of the apoptotic
cascade in hepatocytes, the magnitude of which strongly correlates to the absolute amount
of the a1AT mutant Z protein accumulated within the individual cell. Increases in apoptotic
regulatory proteins are also detected. These data, combined with previous work, permit for
the first time the construction of a hypothetical hepatocellular injury cascade for this disease
involving mitochondrial injury, caspase activation, and apoptosis, which takes into account
the heterogeneous nature of the mutant Z protein accumulation within the liver. Further
development of this hypothetical cascade will focus future research on this and other metabolic
liver diseases.

Patent: None

References:

Lindblad D, Blomenkamp K, Teckman J. Alpha-1-antitrypsin mutant Z protein content in
individual hepatocytes correlates with cell death in a mouse model. Hepatology. 2007
Oct;46(4):1228-35.

Rudnick D, Muglia L, Perlmutter DH, Teckman JH. Hepatocellular Proliferation in a mouse model of alpha-1-antitryspin deficiency.  Hepatology 2004;39(4):1048.

 An JK, Blomenkamp K, Lindblad DL, Teckman JH. Quantitative isolation of alpha-1-antirypsin mutant Z protein polymers from human and mouse livers and the effect of heat.  Hepatology 2004. 41:160-167

Rudnick DR, Blomenkamp K, Teckman JH.  Indomethacin is associated with increased  liver injury in a mouse model of alpha-1 AT deficiency liver injury. Hepatology 2006. 44(4):976.

 Cruz P, Cossette T, Golant A, Tang Q, Beattie S, Brantly M, Campbell-Thompson M, Teckman JH, and Flotte T.  In Vivo Posttranscriptional Gene Silencing of Alpha 1 Antitrypsin by Adeno-Associated Virus Vectors Expressing siRNA. Laboratory Investigation 2007. 87(9): p. 893-902.

  Lindblad D, Blomenkamp K, Teckman JH.  Alpha-1-antitrypsin Mutant Z Protein Content in Individual Hepatocytes Correlates with Cell Death in a Mouse Model. Hepatology 2007. 46(4): p. 1228-35.

  Kaushal S, Annimali M, Blomenkamp K, Ahmed M, Rudnick D, Halloran D, Brunt EM, Teckman JH. Rapamycin reduces hepatic alpha-1-antitrypsin mutant Z protein polymers in a mouse model. Experimental Biology and Medicine. 2010 Jun;235(6):700-9..

  Marcus N, Brunt EB, Blomenkamp K, Ali F, Rudnick D, Ahmed M, Teckman JH. Hepatocellular Carcinoma in a model of alpha-1-antitrypsin deficiency. Hepatology Research, 2010, 40:641-653.

  Brunt EB, Blomenkamp K, Ali F, Marcus N, Ahmed M, Teckman JH. Hepatic Progenitor Cell Proliferation and Liver Injury in Alpha-1-antitrypsin Deficiency. Journal of Pediatric Gastroenterology and Nutrition, 2010; 51: p626-630.

  Mueller C, Tang Q, Gruntman A, Blomenkamp K, Teckman J, Song L, Zamore, PD, Flotte TR. Sustained miRNA-mediated Knockdown of Mutant AAT With Simultaneous Augmentation of Wild-type AAT Has Minimal Effect on Global Liver miRNA Profiles. Molecular Therapy (2012) (in press).

 Marcus N, Blomenkamp K, Ahmed M, Teckman J. Oxidative damage contributes to liver injury in a model of alpha-1-antitrypsin deficiency. Experimental Biology and Med. (2012) in press.

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Stephanie Kimzey, MBA

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