Description:
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.
Manager:
Stephanie Kimzey, MBA
Office
of Technology Management
Fusz
Hall, Suite 253
Phone:
314-977-7731
Fax:
314-977-1008
kimzeysl@slu.edu