Overdose of acetaminophen (APAP), the popular analgesic and antipyretic agent, is the most common cause of acute liver failure (ALF) in the developing countries. Treatment options for APAP-induced ALF are extremely limited. Most ALF patients are treated with N-acetyl cystein, a precursor of glutathione, which works only if delivered within hours after APAP overdose. The only other therapy is liver transplantation, which is complicated by scarcity of donor organs, life long immunosuppressant use and exorbitant cost. There is a critical need to develop novel therapies for APAP-induced ALF. Recent studies in animal models and patients have demonstrated that timely stimulation of innate liver regeneration is associated with better outcomes including transplant free survival in APAP-induced ALF. These studies indicate that without proper liver regeneration APAP-induced acute liver injury can develop into ALF and result in death. Whereas these reports have underscored the therapeutic potential of liver regeneration following APAP-induced ALF, the mechanisms of liver regeneration after APAP overdose are not completely known. Our preliminary studies indicate that canonical Wnt signaling culminating in -catenin activation plays a critical role in liver regeneration after APAP- induced ALF and could be used for therapeutic targeting. The studies in the first specific aim will determine the role of each component of canonical Wnt pathway including -catenin, GSK3, disheveled, Lrp5 and Wnt4 in liver regeneration after ALF. Another significant problem in developing regenerative therapies for ALF is the lack of reliable and easy to use biomarkers of liver regeneration. Currently, there are no reliable biomarkers that can be easily measured in serum of ALF patients, which can reveal the status of innate liver regeneration in ALF patients. Predictive models that factor in biomarkers of regeneration will allow clinicians to track status of patient's innate liver regeneration and aid in decisions on listing for transplantation. Our preliminary data indicate tha serum levels of leukocyte derived chemotaxin-2 (Lect2) could be used as a reliable biomarker of liver regeneration following acute liver failure. These studies will not only determine the role of Lect2 as a biomarker of regeneration in ALF but also determine role of Lect2 in stimulation of hepatocyte proliferation providing an additional therapeutic target. Overall, the studies in this grant proposal will determine the mechanisms of liver regeneration and identify novel biomarkers of liver regeneration specific to APAP-induced ALF. Successful completion of these studies will have substantial impact on clinical management of APAP-induced ALF patients.

Public Health Relevance

The proposed research is relevant to public health because determining the mechanisms of liver regeneration following acetaminophen-induced acute liver failure will help identify new therapeutic targets. The objectives of this grant are to determine te role of canonical Wnt signaling pathway in stimulating liver regeneration following acetaminophen induced acute liver failure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK098414-03
Application #
8826109
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (05))
Program Officer
Serrano, Jose
Project Start
2013-04-01
Project End
2018-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
3
Fiscal Year
2015
Total Cost
$328,425
Indirect Cost
$110,925
Name
University of Kansas
Department
Pharmacology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Singh, Vivekanand; Manalang, Michelle; Singh, Meenal et al. (2018) A Brief Report of Immunohistochemical Markers to Identify Aggressive Hepatoblastoma. Appl Immunohistochem Mol Morphol 26:654-657
Borude, Prachi; Bhushan, Bharat; Apte, Udayan (2018) DNA Damage Response Regulates Initiation of Liver Regeneration Following Acetaminophen Overdose. Gene Expr 18:115-123
Huck, Ian; Beggs, Kevin; Apte, Udayan (2018) Paradoxical Protective Effect of Perfluorooctanesulfonic Acid Against High-Fat Diet-Induced Hepatic Steatosis in Mice. Int J Toxicol 37:383-392
McCracken, Jennifer M; Chalise, Prabhakar; Briley, Shawn M et al. (2017) C57BL/6 Substrains Exhibit Different Responses to Acute Carbon Tetrachloride Exposure: Implications for Work Involving Transgenic Mice. Gene Expr 17:187-205
McGreal, Steven R; Rumi, Karim; Soares, Michael J et al. (2017) Disruption of Estrogen Receptor Alpha in Rats Results in Faster Initiation of Compensatory Regeneration Despite Higher Liver Injury After Carbon Tetrachloride Treatment. Int J Toxicol 36:199-206
Bhushan, Bharat; Poudel, Samikshya; Manley Jr, Michael W et al. (2017) Inhibition of Glycogen Synthase Kinase 3 Accelerated Liver Regeneration after Acetaminophen-Induced Hepatotoxicity in Mice. Am J Pathol 187:543-552
Apte, Udayan; Kaplowitz, Neil (2017) Heparan sulfate promotes recovery from acute liver injury: Inhibition of progressive cell death or enhanced regeneration? Hepatology 66:1381-1383
Bhushan, Bharat; Chavan, Hemantkumar; Borude, Prachi et al. (2017) Dual Role of Epidermal Growth Factor Receptor in Liver Injury and Regeneration after Acetaminophen Overdose in Mice. Toxicol Sci 155:363-378
Jiang, Lu; Sun, Lina; Edwards, Genea et al. (2017) Increased YAP Activation Is Associated With Hepatic Cyst Epithelial Cell Proliferation in ARPKD/CHF. Gene Expr 17:313-326
Tan, Ee Phie; McGreal, Steven R; Graw, Stefan et al. (2017) Sustained O-GlcNAcylation reprograms mitochondrial function to regulate energy metabolism. J Biol Chem 292:14940-14962

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