BLR&D Research Career Scientist Award Application

Va Greater Los Angeles Healthcare System, Los Angeles CA

Investigators

Linked publications & trials

Abstract

This application is for a competitive renewal of the SCRS program of Dr. Hidekazu (Hide) Tsukamoto. Dr. Tsukamoto continues to make significant contributions to the Medical Research Program of the Department of Veterans Affairs via two distinct yet interactive efforts: firstly as a Research Physiologist who gains novel insights into molecular and cellular mechanisms of liver fibrosis, alcohol-associated hepatitis (AH) and liver cancer; and secondly as a Center Director of the NIH P50 national center program on alcohol-associated liver and pancreatic diseases (ALPD) and cirrhosis, providing concrete and outcome-oriented support for scientific endeavors pursued by VA investigators regionally and across the nation. He published 56 peer-review articles and 9 reviews and book chapters in the past 10 years, acquired a new multiple-PI U01 grant on immunosuppressive mechanisms responsible for alcohol-associated liver cancer in 2018 and a multiple-PI R01 grant on hepatocyte-derived extracellular vesicles in alcohol-associated liver disease (ALD) in 2020; renewed VA Merit Review on cellular and molecular mechanisms of hepatic stellate cell (HSC) activation in liver fibrosis in 2022 and the P50 ALPD center grant in 2024; and most recently obtained a new R01 grant on CYP1B1+PRRX1+RN4A2+ HSC in alcohol-associated hepatitis in August 2024 (2 percentile impact score). His team has uncovered the obligatory role of β-catenin (CTNNB1) in myofibroblastic cell fate regulation of hepatic stellate cells (HSC) in liver fibrogenesis via its ability to upregulate stearoyl-CoA desaturase 2 (SCD2) which in turn renders a novel positive forward regulation for the CTNNB1-WNT pathway through the WNT co-receptor LRP5/6 stabilization (Gastroenterology 2017;152:1477). This SCD2-dependent mechanism has recently been extended to liver tumor development in which the oxylipin 12-HHTrE released by HSC in a SCD2-dependet manner, was shown to sequentially activate CTNNB1 and YAP1 in tumor cells for their growth. As such, genetic knockdown of the cognate oxylipin receptor LTB4R2, suppressed liver tumor growth in mice and in patient HCC organoids (Nature Comm 2023;14:2651). His research also disclosed a novel HSC subpopulation which co- expresses the HSC marker Lrat and the portal fibroblast marker Fbln2 and this “hybrid” subpopulation is implicated as the most profibrotic and pro-inflammatory subset in alcohol-associated hepatitis (Hepatology 2023;78:212) and as the source of the aforementioned tumor-promoting oxylipin in alcohol-promoted liver cancer. These findings are shaping a framework of a new therapeutic modality directed toward the novel HSC subpopulation for both diseases. His programmatic efforts via the P50 ALPD center, have supported 10 VA investigators at the regional and national levels in the past seven years and facilitated their 8 federal grants and 9 collaborative publications. Integrative Liver Cell Core (R24 AA012885) which he directs, is strategically integrated with the ALPD center’s Animal Core to offer unique and invaluable services of isolation of 6 liver cell types from the mouse models of ALD, provision of extracellular vesicles released by such cells; and genetic tracing and targeting of three cell types in such models. Collectively, these programmatic mechanisms have supported many VA and non-VA scientists for their investigational endeavors. In essence, Dr. Tsukamoto’s individual and programmatic contributions continue to make significant impacts on science pursued by VA investigators including himself and help identify novel therapeutic targets for ALD, cirrhosis and liver cancer which are prevalent and high-priority diseases for VA healthcare.