Dr. Hidekazu (Hide) Tsukamoto continues to make significant contributions to the Medical Research Program of the Department of Veterans Affairs at two distinct levels: first as a Research Physiologist who makes cutting-edge discoveries on molecular cellular mechanisms of liver fibrosis and cancer; and secondly as a Center Director of the P50 national center program on alcoholic liver and pancreatic diseases (ALPD) and cirrhosis who renders concrete and outcome-oriented support for scientific endeavors of VA investigators regionally and across the nation. He published 71 peer-review articles in the last 10 years and maintained federal grants with total current direct costs exceeding $1.1M per year (not inclusive of all center components). He has made major contributions to new knowledge concerning morphogen-mediated regulation of cell fate of hepatic stellate cells (HSCs), hepatic macrophages, and tumor-initiating stem-like cells (TICs), the cell types shown to play critical roles in liver fibrosis, inflammation, and cancer, respectively. In these regulations, novel modes of metabolic reprogramming were disclosed as underlying mechanisms. More specifically, Notch-mediated proinflammatory M1 activation of liver macrophages is causally linked to mitochondrial metabolic reprogramming (J Clin Invest 2015;125:1579-90). Wnt-induced activation of HSCs is mediated by lipid metabolic reprogramming involving stearoyl CoA desaturase (SCD) (Gastroenterology 2017;152:1477-91). Further, SCD expressed by HSCs is shown to achieve tumor-promoting lipid reprogramming in microenvironment to enhance liver tumor progression. Programmatically, he continues to direct a nationally renowned P50 center program on alcoholic liver and pancreatic diseases and a R24 core program on integrative liver cell techniques which support leading-edge ALPD research. Through these programs, he collaborated and supported 12 VA investigators and mentored 10 junior faculty members during the current cycle of the VARCS award. In essence, the efforts Dr. Tsukamoto makes, render individual and collective impacts on science pursed by him and many VA investigators across the nation and help identify therapeutic targets for ALPD and cirrhosis which are prevalent in VA patients.
Dr. Tsukamoto?s ongoing research is aimed at better understanding of molecular mechanisms underlying activation of the liver cell type called hepatic stellate cells (HSCs) which cause cirrhosis and promote liver cancer. His research has discovered HSCs promote both liver fibrosis and tumor development by actions of the enzyme called stearoyl Co-A desaturase (SCD). Proposed research will aim to elucidate how this tumor promotion takes place using the genetic mouse models, global screening for lipids in tumor microenvironment, and analysis of gene regulation. These efforts will help identify new therapeutic targets for cirrhosis and liver cancer which are common complications of chronic liver disease among veteran patients. !