Treating AT deficiency with drugs that modulate the proteoatasis network

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PROJECT SUMMARY (See instructions): The classical form of al antitrypsin deficiency (ATD) is one of the most common genetic causes of liver disease. Liver transplantation represents the only treatment currently available for severe liver disease due to ATD. The liver disease associated with ATD is characterized by a stereotypical chronic fibrosis leading to cirrhosis and hepatocyte hyper-proliferation that predisposes to hepatocellular carcinoma. This pathology is attributed to the proteotoxic effect of mutant AT Z that accumulates in the endoplasmic reticulum (ER) of liver cells, a gain-of-toxic function mechanism specific for the polymerogenic tendencies of mutant ATZ. My lab has elucidated the potential mechanisms by which liver cells cope with the proteotoxic effects of ATZ accumulation in the ER including a distinct set of intracellular degradation pathways (proteasomal and autophagic) and a distinct set of signaling pathways that are specifically activated (autophagy, NFKB, ER- and mitochondrial-caspases but not the unfolded protein response). Our working hypothesis is that pharmacological strategies which capitalize on these naturally occurring, presumably protective proteostasis regulatory mechanisms will have a therapeutic effect on the liver disease caused by ATD. Recently, we validated this hypothesis by showing that an autophagy enhancer drug , carbamazepine (CBZ), promotes degradation of ATZ, reduces the hepatic ATZ load and hepatic fibrosis in vivo in a mouse model of ATD. In the work proposed in this application we will pursue this hypothesis further by investigating other drug candidates with putative actions specifically on the autophagy or on the proteasomal system as well as drug candidates such as histone deacetylase inhibitors which may affect the proteostasis network by broad actions on the cellular transcriptome The project will also capitalize on a C. elegans ATD model-based high content screening platform together with computational pharmacological analyses to discover additional therapeutic candidates. Finally, we will investigate the role of other cellular response pathways, such as NFKB signaling, caspase 12, SIDT2 and PIS kinase, in the pathologic effects of ATD to determine whether these pathways could be exploited for novel therapeutic strategies in the future.