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American Liver Foundation
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New York, New York 10006
AASLD/ALF Liver Scholar Award
University of Kansas Medical Center, Kansas City, Kansas
Wnt/β-catenin Signaling in Liver Regeneration following Acetaminophen-induced Acute Liver Failure
Acetaminophen (APAP)-induced acute liver failure (ALF) is a major clinical problem and the leading cause of ALF in the Western world. More than 50% of all ALF cases in the US are due to APAP overdose with close to 35% mortality. Current therapies include treatment of N-acetylcystein, a precursor of glutathione, which serves as a primary defense against NAPQI, the reactive metabolite of APAP; and liver transplantation. Both these treatment options have limited success and added complications. This has led to search for novel therapies against this devastating problem. In recent years regenerative therapies focused on stimulating regeneration in the remaining tissue have gained considerable attention. Liver is known for its remarkable capacity to regenerate following surgical resection or after drug overdose. Studies have shown that patients with strong regenerative response have better prognosis following APAP overdose. However, no systematic study has been conducted to investigate the potential of regenerative therapies against APAP-induced acute liver failure.
Dr. Apte will investigate the dynamics of liver regeneration following APAP overdose and will investigate novel regeneration-based treatment strategies with emphasis on Wnt/β-catenin signaling pathway. Preliminary studies indicate that β-catenin, a downstream effector of the Wnt/ β -catenin pathway, and a protein involved in liver development, differentiation and regeneration is rapidly activated following APAP–induced ALF and is involved in stimulating regeneration. Dr. Apte will investigate the mechanism by which β -catenin stimulates regeneration following APAP-induced liver injury and determine the effectiveness of various growth factors known to stimulate liver cell proliferation via β -catenin activation in treatment of APAP-induced ALF. Additionally, Dr. Apte will evaluate two β -catenin target genes, which are detectable in the serum, as biomarkers of regeneration following ALF. These studies will be conducted using well-established mouse models of APAP-induced ALF combined with state-of-the-art techniques such as ChIP-on-Chip assays, in vivo gene delivery and using a large repository of patient serum samples from the NIH-sponsored Multicenter Acute Liver Failure Study.
Dr. Apte anticipates that the results of these studies will reveal a mechanism-based role of β -catenin in stimulation of liver regeneration in victims of ALF and provide basis for future investigations in developing specific regenerative therapies. The main outcome of Dr. Apte’s studies will be highlighting the efficacy of the regenerative therapies for ALF and identifying novel biomarkers that will help clinicians to make critical decisions about patient care.