This program project will discover and test novel compounds as potential therapeutic agents, as well as test and discover signaling pathways as potential modifiers, of liver disease due to ?1-antitrypsin deficiency (ATD), one of the most common genetic causes of liver disease and a frequent indication for liver transplantation. The program project grew out 4 collaborations: collaboration between Drs. Perlmutter, Michalopoulos and Stolz showed that, by enhancing autophagic degradation of mutant ATZ, carbamazepine could reduce hepatic ATZ load and fibrosis in the PiZ mouse model of ATD, and therein provided evidence that endogenous proteostasis mechanisms could be targeted for therapeutics;collaboration between Drs Silverman and Perlmutter using a newly developed C. elegans model of ATD and a high-content screening platform generated a powerful engine for discovery of additional drugs and modifiers;collaboration between Drs. Bahar, Silverman and Perlmutter has added computational pharmacological strategies to potential drug discovery for ATD;collaboration between Drs. Fox, Chowdhury and Perlmutter has shown that transplanted hepatocytes will re-populate the liver of the PiZ mouse model of ATD, providing the potential for developing 'humanized'mouse models of ATD with the ultimate goal of personalized medicine for ATD. The 4 projects include: 1) testing of novel drug and modifier candidates in mammalian cell line and mouse models of ATD (Pl-Perlmutter);2) use of the C. elegans model of ATD to discover new drugs and modifiers (Pl-Silverman);3) use of sophisticated pathologic and genomic approaches to elucidate mechanisms of hepatocyte hyperproliferation in mouse models of ATD (Pl-Michalopoulos);4) repopulation studies using a new immunedeficient PiZ mouse model and iPS cell lines to develop 'humanized'mice that model ATD together with host-specific modifiers (co-PIs: Fox;Chowdhury). The S cores include: A) Cell and Tissue Imaging (Pl- Stolz);B) Computational Pharmacology (Pl-Bahar);C) Genomics (Pi-Bell). This outstanding group of investigators will use existing and develop novel model systems which together with sophisticated drug discovery tools, pathologic and genomic techniques will lead to new drugs and druggable targets for ATD.

Public Health Relevance

The studies proposed in this application will use multiple model systems and analytical techniques to test potential therapeutic agents that are currently available as well as discover new drugs and novel druggable targets for ?1 antitrypsin deficiency, one of the most common genetic causes of hepatic fibrosis, cirrhosis and carcinoma in humans.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
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Special Emphasis Panel (ZDK1-GRB-8 (O1))
Program Officer
Doo, Edward
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University of Pittsburgh
Schools of Medicine
United States
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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 ?1-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 ?1-antitrypsin deficiency links components of the RNAi pathway to misfolded protein turnover. Hum Mol Genet 23:5109-22
Miedel, Mark T; Zeng, Xuemei; Yates, Nathan A et al. (2014) Isolation of serpin-interacting proteins in C. elegans using protein affinity purification. Methods 68:536-41
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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
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
Li, Jie; Pak, Stephen C; O'Reilly, Linda P et al. (2014) Fluphenazine reduces proteotoxicity in C. elegans and mammalian models of alpha-1-antitrypsin deficiency. PLoS One 9:e87260
Fox, Ira J; Daley, George Q; Goldman, Steven A et al. (2014) Stem cell therapy. Use of differentiated pluripotent stem cells as replacement therapy for treating disease. Science 345:1247391
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

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