Dr. Sergio Attanasio
Therapeutic strategies to reduce hepatic proteotoxic mutant Z α1-antitrypsin
Background: A1AT deficiency (AATD) is an important genetic cause of liver disease. The majority of the affected patients carry the Z allele (ATZ). The spectrum of liver disease varies enormously and it includes asymptomatic states, fibrosis, cirrhosis and increased risk of hepatocellular carcinoma (HCC). Currently, there are no drug-based therapies for the liver disease and severely affected can only be treated with liver transplantation. Therefore, novel treatments are urgently needed. A1AT is an acute-phase protein and is upregulated by cytokines IL-6 and TNFα. In my preliminary studies, I found that Tnfα expression is increased in livers of the PiZ mice, a transgenic mouse model expressing human ATZ that ricapitulates tha human hepatic disease. Therefore, I hypothesize that TNFα upregulation aggravates ATZ-mediated liver injury by increasing SERPINA1 expression. Moreover, I found upregulation of the autophagy receptor p62. In addition, I found that p62 co-localizes and binds to ATZ. Inclusion bodies with p62 have been found in several proteinopathies. Moreover, p62 regulates liver tumorigenesis by activating multiple signalling pathways.
The main goal of my proposal is to test the efficacy of a FDA-approved anti-TNFα agent for therapy of liver disease induced by ATZ. I will also investigate the role of p62 in the pathogenesis of liver disease associated to AATD.
The proposed studies have the potential to provide a novel treatment for ATZ-related liver disease that could be rapidly translated into human applications because this approach is based on an already approved drug. Moreover, it has the potential to shed light on the mechanisms involved in ATZ accumulation and toxicity.
Curriculum vitae Dr. Sergio Attanasio
Sergio graduaded with honors in Molecular Biology at the "Federico II" University of Naples, Italy. Then, he started his PhD at the Telethon Institute of Genetics and Medicine (TIGEM), Italy. The main topic of his research has been focused on the understanding of the molecular mechanisms involved in the pathogenesis of the liver disease induced by mutant Z alpha1 antitrypsin (Z-AAT) and to develop novel therapeutic strategies for this disorder. During his Ph.D., he found that c-Jun N-terminal kinase (JNK) is induced in livers by mutant Z-AAT. Moreover, he found that JNK inhibitors reduce hepatic accumulation of Z-AAT. He is currently III-year PhD student and he is expected to discuss his PhD thesis next October 2018.
His Project "Therapeutic strategies to reduce hepatic proteotoxic mutant Z α1-antitrypsin" aims to provide a novel therapeutic approach for treatment of liver disease associated to AATD and to investigate the molecular mechanisms underlying hepatocyte damage induced by ATZ.