The classical form of a1-antitrypsin (AT) deficiency is the most common genetic cause of liver disease in children and also predisposes adults to liver damage. In this deficiency a point mutation renders a hepatic secretory protein prone to misfolding and aggregation. The mutant protein, a1-antitrypsin Z (ATZ), accumulates in the endoplasmic reticulum (ER) of liver cells, causing inflammation and carcinogenesis by a gain-of-toxic function mechanism. The investigators now know that there are two general mechanisms by which the quality control apparatus of the ER degrades this mutant protein when it accumulates in that compartment: the proteasomal pathway is responsible for disposal of soluble ATZ and the autophagic pathway is responsible for disposal of insoluble aggregated ATZ that is retained in the ER. Presumably the accumulation of mutant ATZ and its hepatotoxic effects reflect an inability of proteasomal and autophagic disposal pathways to handle the mutant protein load. In this application the investigators will examine the hypothesis that pharmacological enhancement of the function of the disposable pathways prevents and ameliorates the liver disease of AT deficiency using a newly developed genetically engineered mouse model of AT deficiency with severe liver damage. Preliminary evidence for three novel strategies is presented and will be further examined using a series of preclinical studies in the mouse model: stimulation of the insulin signaling pathway that enhances autophagic disposal of ATZ through a TOR kinase-independent mechanism;stimulation of autophagic disposal of ATZ by drugs that are already approved for use in humans by the FDA and appear to work by insulin-independent and TOR kinase-independent mechanisms;stimulation of proteasomal degradation of ATZ using a peptide with a specific depolymerizing effect on ATZ. The studies proposed in this application have the potential to rapidly move into clinical trials of pharmacological strategies for a liver disease that is currently only amenable to liver transplantation therapy. NARRATIVE: This application proposes preclinical studies of three novel pharmacological strategies for preventing or treating chronic hepatitis and hepatocellular carcinoma associated with a1-antitrypsin deficiency, the most common genetic liver disease of children.

Public Health Relevance

The application proposes pre-clinical studies of 3 novel pharmacological strategies for preventing/treating chronic hepatitis and hepatocellular carcinoma associated with ?1 - antitrypsin deficiency, the most common genetic liver disease of children.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK084512-04
Application #
8274750
Study Section
Special Emphasis Panel (ZHD1-MRG-C (21))
Program Officer
Doo, Edward
Project Start
2009-05-10
Project End
2013-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$359,319
Indirect Cost
$122,145
Name
University of Pittsburgh
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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