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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23AA018399-04
Application #
8451595
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Wang, Joe
Project Start
2010-04-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
4
Fiscal Year
2013
Total Cost
$186,738
Indirect Cost
$12,831
Name
University of Louisville
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
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
Wahlang, Banrida; Falkner, K Cameron; Clair, Heather B et al. (2014) Human receptor activation by aroclor 1260, a polychlorinated biphenyl mixture. Toxicol Sci 140:283-97
Wahlang, Banrida; Falkner, K Cameron; Gregory, Bonnie et al. (2013) Polychlorinated biphenyl 153 is a diet-dependent obesogen that worsens nonalcoholic fatty liver disease in male C57BL6/J mice. J Nutr Biochem 24:1587-95
Wahlang, Banrida; Beier, Juliane I; Clair, Heather B et al. (2013) Toxicant-associated steatohepatitis. Toxicol Pathol 41:343-60
Mohammad, Mohammad K; Mohommad, Mohammad K; Zhou, Zhanxiang et al. (2012) Zinc and liver disease. Nutr Clin Pract 27:8-20
Cave, Matt; Falkner, Keith Cameron; Henry, Latasha et al. (2011) Serum cytokeratin 18 and cytokine elevations suggest a high prevalence of occupational liver disease in highly exposed elastomer/polymer workers. J Occup Environ Med 53:1128-33
Kirpich, Irina A; Gobejishvili, Leila N; Bon Homme, Marjorie et al. (2011) Integrated hepatic transcriptome and proteome analysis of mice with high-fat diet-induced nonalcoholic fatty liver disease. J Nutr Biochem 22:38-45
Cave, Matt; Appana, Savitri; Patel, Mihir et al. (2010) Polychlorinated biphenyls, lead, and mercury are associated with liver disease in American adults: NHANES 2003-2004. Environ Health Perspect 118:1735-42
Kazemi, Ali; Frazier, Thomas; Cave, Matt (2010) Micronutrient-related neurologic complications following bariatric surgery. Curr Gastroenterol Rep 12:288-95