In the classical form of ?1antitrypsin deficiency (ATD) a point mutation leads to misfolding of a hepatic secretory protein and the variant, ?1antitrypsin Z (ATZ), accumulates in the ER of liver cells as polymers and aggregates. Liver fibrosis and hepatocellular carcinoma develops in a subgroup of affected homozygotes by a gain-of-function 'proteotoxic'mechanism. There is wide variability in the hepatic phenotype with ~10% affected in infancy/early childhood and another subgroup that develop liver disease in the 6th-7th decade of life by an apparent age-dependent process. The central hypothesis of our research has 3 components: 1) variability in hepatic phenotype is determined by genetic and environmental modifiers;2) the targets of these modifiers are the quality control mechanisms of the ER, part of the cell's proteostasis regulatory network;3) the 2 major types of protestasis mechanisms are protein degradation pathways, such as the proteasome and autophagy, and signaling pathways that are designed to protect cells from proteotoxicity. In this grant we propose investigation of the role of 3 signaling pathways that are putative proteostasis regulatory mechanisms designed to prevent liver damage, including the insulin and NF?B signaling pathways as well as the regulator of G signaling 16 (RGS16). The proposal is based on preliminary results showing that these 3 pathways are activated in unique ways in several model systems including mammalian cell line and mouse models with inducible expression of ATZ and a novel C. elegans model that facilitates mechanistic interrogation through rapid genetic engineering and drug discovery. We will determine how these pathways are activated and how they affect the hepatic phenotype of ATD by utilizing novel mouse models with targeted disruption of each pathway as well as by pharmacological strategies that influence the pathways. We will also determine whether there is variation in activation of these pathways among individual patients with ATD using iPS-derived hepatocyte cell lines.

Public Health Relevance

These studies are designed to advance our understanding of the factors that lead to more severe liver disease in AT deficiency and the potential to target these factors for novel therapeutic strategies.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Hepatobiliary Pathophysiology Study Section (HBPP)
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Doo, Edward
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University of Pittsburgh
Schools of Medicine
United States
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Perlmutter, David H (2016) ?1-antitrypsin Deficiency: A Misfolded Secretory Protein Variant with Unique Effects on the Endoplasmic Reticulum. Endoplasmic Reticulum Stress Dis 3:63-72
Perlmutter, David H (2016) Current and Emerging Treatments for Alpha-1 Antitrypsin Deficiency. Gastroenterol Hepatol (N Y) 12:446-8
Chu, Andrew S; Chopra, Kapil B; Perlmutter, David H (2016) Is severe progressive liver disease caused by alpha-1-antitrypsin deficiency more common in children or adults? Liver Transpl 22:886-94
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