Our longstanding work demonstrates that A20 (tnfaip3) enhances the liver's combined anti-inflammatory, anti- apoptotic, and anti-oxidant response to injury, and promotes hepatocyte proliferation and liver regeneration. In experimental animal models, we have shown that overexpression of A20 in the liver is protective following radical lethal hepatectomy and severe liver ischemia reperfusion injury, and allows for successful engraftment of marginal liver transplants. Loss-of-function experiments further confirmed the essential physiologic role of A20 in supporting liver regeneration. Indeed, we showed that partial A20 knockdown, as seen in heterozygote mice (A20 ) significantly impairs liver regeneration and increases lethality following 2/3 partial hepatectomy. Recently, in human genome-wide association studies, tnfaip3 gene polymorphisms have been identified as susceptibility loci for several inflammatory and autoimmune diseases. In this proposal, we wish to determine whether A20 gene polymorphisms and the expression level of A20 and of its target genes in the graft could serve as reliable prognostic markers for liver regeneration and function in living donor liver transplantation (LDLT). LDLT has emerged as a solution to ease the shortage of organs available for orthotopic liver transplantation (OLT). However its widespread use in adults is limited by the size of the graft that can be safely harvested. Biomarkers that would limit the risk to the donor while improving graft success are direly needed to allow for safe expansion of the field, which would help in easing the severe shortage of organs that are available for OLT. We plan to: 1. Probe for tnfaip3 gene polymorphisms in all living liver donors. 2. Evaluate the expression levels of A20 and of its target genes in liver transplant biopsies before liver transplantation, and in the prospective cohort of patients, after reperfusion (recipient), or before the end of surgery (donor). As part of this aim, we will also determine A20 mRNA and protein levels using peripheral blood mononuclear cells from the donor. 3. Measure circulating levels of priming cytokines (TNF and IL-6) in recipient and donor sera before and after graft reperfusion (recipient) or liver resection (donor). 4. Correlate tnfaip3 gene polymorphisms, A20 expression levels, and expression levels of its target genes with circulating levels of priming cytokines, and regeneration status, as determined by Dynamic Contrast Enhanced Multi-Detector CT (DCE-MDCT) with subsequent qualitative and quantitative 3D analysis and MeVis reconstruction, liver function (liver enzymes, and coagulation tests), and early clinical outcomes (time to discharge, primary dysfunction, need for re-transplantation). Data gathered in this work will promote the use of A20 gene polymorphisms and expression levels as reliable selection markers for pairing donors and recipients in LDLT to reduce donor morbidity and improve recipient outcomes.

Public Health Relevance

Orthotopic liver transplantation (OLT) is a life-saving measure for patients suffering from acute or chronic liver failure. However, demand greatly exceeds organ availability, causing a number of patients to die while on the waiting list. Living donor liver transplantation (LDLT) has emerged as a solution to ease the shortage in organs that are available for OLT. However, in adults, LDLT is limited by the size of the graft that can be safely harvested. Expression levels and function of the hepatoprotective protein A20, as determined by tnfaip3/A20 gene polymorphisms, are promising tools that can be used as selection biomarkers for pairing donors and recipients in LDLT, which would reduce donor morbidity and improve recipient outcomes. Validation of A20 as a reliable prognostic biomarker in LDLT could serve as an objective measure of donor adequacy and could help to expand the field of LDLT, split livers and OLT in general.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-DKUS-D (80))
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Sherker, Averell H
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Beth Israel Deaconess Medical Center
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Moll, Herwig P; Lee, Andy; Peterson, Clayton R et al. (2016) A20 Haploinsufficiency Aggravates Transplant Arteriosclerosis in Mouse Vascular Allografts: Implications for Clinical Transplantation. Transplantation 100:e106-e116
da Silva, Cleide Gonçalves; Minussi, Darlan Conterno; Ferran, Christiane et al. (2014) A20 expressing tumors and anticancer drug resistance. Adv Exp Med Biol 809:65-81
McGillicuddy, Fiona C; Moll, Herwig P; Farouk, Samira et al. (2014) Translational studies of A20 in atherosclerosis and cardiovascular disease. Adv Exp Med Biol 809:83-101
da Silva, Cleide G; Studer, Peter; Skroch, Marco et al. (2013) A20 promotes liver regeneration by decreasing SOCS3 expression to enhance IL-6/STAT3 proliferative signals. Hepatology 57:2014-25