Alpha-1 antitrypsin deficiency is a common single-gene disorder, in which the most common mutant "Z" allele (Glu342Lys) occurs with remarkably high frequency in Northern Europeans and North Americans. Homozygous Z patients suffer from a lung disease that is due to the lack of normal antiprotease function of the wild-type AAT, and may also suffer from a liver disease, that appears to be triggered by retention of polymeric and/or aggregated Z-AAT protein within hepatocytes. A mouse model expressing the human Z-allele has utility in examining molecular endpoints but does not faithfully reproduce the inflammation and cirrhosis observed in severely affected patients. In this application, we propose to develop better models of AAT-related liver disease using environmental challenges and human stem cell derived liver chimeras, and further to test a combined gene therapy/RNA inhibition strategy as a potential future therapy.
Our first aim will use an ethanol induce hepatotoxicity in mice with the human Z allele to assess the risk of increased risk hepatocellualr carcinoma and to better understand the pro-inflammatory and pro-fibrotic pathways in these livers. This concept will then be extended to studies using humanized mouse livers with either normal or Z-allele positive human liver stem cells derived from iPS cells. Finally both of these models will be utilized to assess the effect of rAAV-based RNAi mediated knockdown of the Z-AAT mRNA.

Public Health Relevance

Alpha-1 antitrypsin deficiency is a common single-gene disorder, in which the most common mutant Z allele (Glu342Lys) occurs with remarkably high frequency in Northern Europeans and North Americans. Homozygous Z patients suffer from a lung disease that is due to the lack of normal antiprotease function of the wild-type AAT, and may also suffer from a liver disease, that appears to be triggered by retention of polymeric and/or aggregated Z-AAT protein within hepatocytes. A mouse model expressing the human Z-allele has utility in examining molecular endpoints but does not faithfully reproduce the inflammation and cirrhosis observed in severely affected patients. In this application, we propose to develop better models of AAT-related liver disease using environmental challenges and human stem cell derived liver chimeras, and further to test a combined gene therapy/RNA inhibition strategy as a potential future therapy.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DK098252-02
Application #
8664375
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Doo, Edward
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
None
Type
Schools of Medicine
DUNS #
City
Worcester
State
MA
Country
United States
Zip Code
01655