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.

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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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZHD1-MRG-C (21))
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Doo, Edward
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University of Pittsburgh
Schools of Medicine
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Hidvegi, Tunda; Stolz, Donna B; Alcorn, John F et al. (2015) Enhancing Autophagy with Drugs or Lung-directed Gene Therapy Reverses the Pathological Effects of Respiratory Epithelial Cell Proteinopathy. J Biol Chem 290:29742-57
O'Reilly, Linda P; Long, Olivia S; Cobanoglu, Murat C et al. (2014) A genome-wide RNAi screen identifies potential drug targets in a C. elegans model of α1-antitrypsin deficiency. Hum Mol Genet 23:5123-32
Long, Olivia S; Benson, Joshua A; Kwak, Joon Hyeok et al. (2014) A C. elegans model of human α1-antitrypsin deficiency links components of the RNAi pathway to misfolded protein turnover. Hum Mol Genet 23:5109-22
O'Reilly, Linda P; Luke, Cliff J; Perlmutter, David H et al. (2014) C. elegans in high-throughput drug discovery. Adv Drug Deliv Rev 69-70:247-53
Chu, Andrew S; Perlmutter, David H; Wang, Yan (2014) Capitalizing on the autophagic response for treatment of liver disease caused by alpha-1-antitrypsin deficiency and other genetic diseases. Biomed Res Int 2014:459823
Ghouse, Raafe; Chu, Andrew; Wang, Yan et al. (2014) Mysteries of α1-antitrypsin deficiency: emerging therapeutic strategies for a challenging disease. Dis Model Mech 7:411-9
O'Reilly, Linda P; Perlmutter, David H; Silverman, Gary A et al. (2014) *1-antitrypsin deficiency and the hepatocytes - an elegans solution to drug discovery. Int J Biochem Cell Biol 47:109-12
Wang, Yan; Perlmutter, David H (2014) Targeting intracellular degradation pathways for treatment of liver disease caused by *1-antitrypsin deficiency. Pediatr Res 75:133-9
Silverman, Gary A; Pak, Stephen C; Perlmutter, David H (2013) Disorders of protein misfolding: alpha-1-antitrypsin deficiency as prototype. J Pediatr 163:320-6
Czaja, Mark J; Ding, Wen-Xing; Donohue Jr, Terrence M et al. (2013) Functions of autophagy in normal and diseased liver. Autophagy 9:1131-58

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