Elucidation of Unfolded Protein Response pathways activated in Lung and Liver Disease associated with Z Alpha-1 Antitrypsin Deficiency

Monday, 24 November 2008 12:41

Health Research Board (HRB)/Medical Research Charities Group (MRCG)

Project Description:

Current treatments for AAT deficiency are based on augmentation therapy with recombinant or plasma-purified AAT and focus almost completely on treating the pulmonary emphysema associated with the disorder. However, the long term efficacy of augmentation therapy has yet to be established, and represents a very expensive therapeutic option. Lung or liver transplantation provides the only effective means of intervention for AAT deficient patients with end-stage lung and liver disease. Unfortunately, while transplantation has been shown to successfully achieve AAT serum conversion, its usefulness as a treatment is confounded by a lack of suitable donors, concomitant immunosuppressive therapy, and high mortality rates. For these reasons it is critically important to develop less invasive therapeutic strategies for the treatment of the lung and liver disease associated with AATD. Conformational diseases are associated with rogue protein accumulation in tissues and cellular compartments. AAT deficiency is one such genetic disease characterised by the accumulation of incorrectly folded AAT in liver cells. The accumulation of mutant Z AAT protein within the cell switches on several protective mechanisms, including the unfolded protein response (UPR). With prolonged activation the UPR becomes harmful to the cell, causes inflammation and ultimately cell death. This is responsible for the cirrhosis observed in the AATD-associated liver disease, but may also be partly responsible for the emphysema seen in AATD-associated lung disease. This may explain why augmentation therapy has yet to be proven clinically effective, and why AAT deficient patients who have received liver transplants still exhibit local inflammation in the lung. We have previously identified intracellular events involved in the molecular pathogenesis of AATD-induced liver disease using an in vitro model system of Z AAT accumulation in liver cells. We will demonstrate that abnormalities in Z AAT-induced liver disease can also be present in Z AAT-induced lung disease. We aim to highlight the crucial involvement of the UPR in Z AAT-associated lung and liver disease. We will show that Z AAT activates the UPR, knocking off protein synthesis, turning on a plethora of UPR-related genes, and activating machinery which degrades the misfolded Z AAT.  We will evaluate the role of UPR mediators in vivo in lung and liver biopsies from individuals with AATD compared to healthy normal individuals.  This discovery-driven project proposal will lead to a greater understanding of AATD, generate several hypotheses, and allow us to identify novel therapeutic avenues for the treatment of AATD-related lung and liver disease.

Duration: 3 years from January 2007