: The Non-Parenchymal Liver Cell Core, now re-named to Integrative Liver Cell Core (ILCC), strives to serve the scientific community of alcoholic liver disease (ALD) and cirrhosis via specialized services of isolation of 6 different lier cell types (hepatocytes, HC; hepatic macrophages, HM; hepatic stellate cells, HSC; liver sinusoidal endothelial cells, LSEC; liver mesothelial cells, MC; and CD133+ liver progenitor cells) from normal rodents and rodent models of ALD and liver fibrosis. To support leading-edge cell type specific research, the ILCC also couples these isolation procedures with the following innovative techniques: 1) Rosa26-reporter-based genetic lineage and cell fate tracing for HC, HSC, and MC in ALD and liver fibrosis; 2) transplantation of monocytes labeled with a fluorescent dye for assessment of transmigration into the liver undergoing alcoholic steatohepatitis (ASH); 3) FACS-based analysis of resident vs. migrating HM to assess their relative contributions to ASH; 4) FACS-based isolation of heterogeneous populations of HSC or vitamin A-depleted HSC from mouse alcoholic liver fibrosis models; and 5) FACS isolation of CD133+ liver progenitors from alcohol-promoted liver cancer and from precancerous alcoholic hepatitis (AH) for investigation on the roles of CD133+ progenitors. To achieve these integrative services, the ILCC effectively collaborates with the Animal Core of the Southern California Research Center for ALPD and Cirrhosis and supports cell type specific analysis including genetic loss or gain of function approaches in rodent models of chronic ASH, AH, alcoholic liver fibrosis, and alcohol-promoted liver cancer. During the current funding cycle, the ILLC has served 31 investigators from 10 institutions by performing 2,204 isolation preparations, supporting 34 publications and acquisition or continuation of 18 NIH grants plus 7 pending applications by a total of 20 investigators. Of these 20 investigators, seven are non-center investigators across the nation, attesting that the ILCC contributes as a national resource. The ILLC has also supported the career development of nine early-career investigators through their cell type-specific research and grant acquisitions (K08, K01, K99R00, three R21s, and two R01s). The proposed ILCC renewal aims to further advance its unique and cutting-edge services of liver cell isolation and analysis and to promote genetic, epigenetic, metabolic, and molecular research on altered cell fate regulation of different liver cell types which manifest as fundamental mechanisms underlying inflammation, fibrosis, and tumorigenesis in ALD.

Public Health Relevance

The proposed renewal of the Integrative Liver Cell Core (ILCC) will promote in-depth research on different liver cell types which are involved in various spectra of liver pathology in alcoholic liver disease (ALD) and liver fibrosis via provision of unique services of isolation and culture of these cells from normal and diseased rodent livers. The ILCC renders these services at the regional and national levels as a NIAAA-supported national resource. The long-term goal of the ILCC is to help scientists develop new therapeutic strategies for ALD and cirrhosis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Resource-Related Research Projects (R24)
Project #
5R24AA012885-17
Application #
9334674
Study Section
Special Emphasis Panel (ZAA1)
Program Officer
Gao, Peter
Project Start
2001-06-01
Project End
2021-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
17
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Southern California
Department
Pathology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90033
Khanova, Elena; Wu, Raymond; Wang, Wen et al. (2018) Pyroptosis by caspase11/4-gasdermin-D pathway in alcoholic hepatitis in mice and patients. Hepatology 67:1737-1753
Gajendiran, Priya; Vega, Leonel Iglesias; Itoh, Kie et al. (2018) Elevated mitochondrial activity distinguishes fibrogenic hepatic stellate cells and sensitizes for selective inhibition by mitotropic doxorubicin. J Cell Mol Med 22:2210-2219
Wu, Raymond; Murali, Ramachandran; Kabe, Yasuaki et al. (2018) Baicalein Targets GTPase-Mediated Autophagy to Eliminate Liver Tumor-Initiating Stem Cell-Like Cells Resistant to mTORC1 Inhibition. Hepatology 68:1726-1740
Zeybel, Müjdat; Luli, Saimir; Sabater, Laura et al. (2017) A Proof-of-Concept for Epigenetic Therapy of Tissue Fibrosis: Inhibition of Liver Fibrosis Progression by 3-Deazaneplanocin A. Mol Ther 25:218-231
Eguchi, Akiko; Lazaro, Raul G; Wang, Jiaohong et al. (2017) Extracellular vesicles released by hepatocytes from gastric infusion model of alcoholic liver disease contain a MicroRNA barcode that can be detected in blood. Hepatology 65:475-490
Chen, Chia-Lin; Huang, Jeffrey Y; Wang, Chun-Hsiang et al. (2017) Hepatitis C virus has a genetically determined lymphotropism through co-receptor B7.2. Nat Commun 8:13882
Yang, Zemin; Liu, Yu; Qin, Lan et al. (2017) Cathepsin H-Mediated Degradation of HDAC4 for Matrix Metalloproteinase Expression in Hepatic Stellate Cells: Implications of Epigenetic Suppression of Matrix Metalloproteinases in Fibrosis through Stabilization of Class IIa Histone Deacetylases. Am J Pathol 187:781-797
Machida, Keigo (2017) Existence of cancer stem cells in hepatocellular carcinoma: myth or reality? Hepatol Int 11:143-147
Lai, Keane K Y; Kweon, Soo-Mi; Chi, Feng et al. (2017) Stearoyl-CoA Desaturase Promotes Liver Fibrosis and Tumor Development in Mice via a Wnt Positive-Signaling Loop by Stabilization of Low-Density Lipoprotein-Receptor-Related Proteins 5 and 6. Gastroenterology 152:1477-1491
Li, Yuchang; Lua, Ingrid; French, Samuel W et al. (2016) Role of TGF-? signaling in differentiation of mesothelial cells to vitamin A-poor hepatic stellate cells in liver fibrosis. Am J Physiol Gastrointest Liver Physiol 310:G262-72

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