This K23 application will enable Matthew Cave, M.D., to achieve his goal of becoming an independent investigator focusing on clinical and translational research in alcoholic liver disease (ALD) and nutrition. Dr. Cave will conduct a mechanistic study evaluating the effects of zinc sulfate therapy in patients with alcoholic cirrhosis (AC). Highlights of Dr. Cave's career development plan include: (i) obtaining a Master of Science degree in Interdisciplinary Studies (I-MS) focusing on toxicology, clinical trial design, and biostatistics, and (ii) board certification in nutrition (ABPNS). These activities will occur in the setting of the recently funded University of Louisville Alcohol Research Center (P01), and will be monitored quarterly by an advisory committee. An estimated two million Americans have ALD, and there are no FDA approved medications for any stage of ALD. Our preliminary data document (i) zinc deficiency in human subjects with AC, and (ii) improvement in liver injury and in postulated mechanisms of liver injury with zinc supplementation in murine models. Our hypothesis is that zinc sulfate therapy will result in improvement in mechanisms postulated to play a role in the development and progression of human AC. To test this hypothesis, we will perform a randomized, double blind, placebo-controlled, """"""""drop in"""""""", mechanistic study of zinc sulfate 220 mg daily in 30 subjects with Child-Pugh A-B AC for 24 months. The primary endpoints are reduction in (i) serum endotoxemia and (ii) ex vivo basal and endotoxin-stimulated TNF1 production. Secondary endpoints are (i) improved serum zinc status, (ii) increased intestinal tight junctions with decreased permeability, (iii) improved serum pro-inflammatory cytokine profile, (iv) reduced oxidative stress and improved serum antioxidant status, (v) reduced hepatocyte death, (vi) decreased fibrosis, and (vii) improved clinical status. These studies utilize state- of-the art techniques in a translational approach to develop an enhanced understanding of a potential new therapy for AC.
This K23 application will enable Matthew Cave, M.D., to achieve his goal of becoming an independent investigator focusing on clinical and translational research in alcoholic liver disease (ALD) and nutrition. We will perform a randomized, double blind, placebo-controlled, drop in, mechanistic study of zinc sulfate 220 mg daily in 30 subjects with Child-Pugh A-B AC for 24 months.
|Hardesty, Josiah E; Wahlang, Banrida; Falkner, K Cameron et al. (2017) Polychlorinated biphenyls disrupt hepatic epidermal growth factor receptor signaling. Xenobiotica 47:807-820|
|Song, Ming; Chen, Theresa; Prough, Russell A et al. (2016) Chronic Alcohol Consumption Causes Liver Injury in High-Fructose-Fed Male Mice Through Enhanced Hepatic Inflammatory Response. Alcohol Clin Exp Res 40:518-28|
|Cave, Matthew C; Clair, Heather B; Hardesty, Josiah E et al. (2016) Nuclear receptors and nonalcoholic fatty liver disease. Biochim Biophys Acta 1859:1083-99|
|Jiang, Mengxi; Klein, Marcus; Zanger, Ulrich M et al. (2016) Inflammatory regulation of steroid sulfatase: A novel mechanism to control estrogen homeostasis and inflammation in chronic liver disease. J Hepatol 64:44-52|
|Liu, Yanlong; Zhao, Cuiqing; Xiao, Jian et al. (2016) Fibroblast growth factor 21 deficiency exacerbates chronic alcohol-induced hepatic steatosis and injury. Sci Rep 6:31026|
|Wahlang, Banrida; Prough, Russell A; Falkner, K Cameron et al. (2016) Polychlorinated Biphenyl-Xenobiotic Nuclear Receptor Interactions Regulate Energy Metabolism, Behavior, and Inflammation in Non-alcoholic-Steatohepatitis. Toxicol Sci 149:396-410|
|Guardiola, John J; Beier, Juliane I; Falkner, K Cameron et al. (2016) Occupational exposures at a polyvinyl chloride production facility are associated with significant changes to the plasma metabolome. Toxicol Appl Pharmacol 313:47-56|
|Kirpich, Irina A; Miller, Matthew E; Cave, Matthew C et al. (2016) Alcoholic Liver Disease: Update on the Role of Dietary Fat. Biomolecules 6:1|
|Al-Eryani, Laila; Wahlang, Banrida; Falkner, K C et al. (2015) Identification of Environmental Chemicals Associated with the Development of Toxicant-associated Fatty Liver Disease in Rodents. Toxicol Pathol 43:482-97|
|Joshi-Barve, Swati; Kirpich, Irina; Cave, Matthew C et al. (2015) Alcoholic, Nonalcoholic, and Toxicant-Associated Steatohepatitis: Mechanistic Similarities and Differences. Cell Mol Gastroenterol Hepatol 1:356-367|
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