Research Themes and Base

Research Themes and Special Interest Groups (SIGs)

Our Center serves as a focal point for faculty from throughout the University who join together with shared interests in Liver Diseases and other aspects of Digestive Diseases which are of common interest in Themes and subthemes, referred to as special interest groups (SIGs). The designation of SIG identifies groups of investigators who interact regularly, cross-collaborate extensively and share methods and resources. Many Center Members are listed in multiple Themes and have funding in separate Theme areas and their interests overlap the science in different Themes such as viral hepatitis/HCC, steatohepatitis, regenerative medicine. Theme coordinators are intimately involved in subthemes (SIGs) in their area.

The current Themes of the Center (since 2013) are the following:

  • Viral Hepatitis and Hepatocellular Carcinoma (Coordinator, James Ou)
  • Steatohepatitis and fibrosis (Coordinator, Hide Tsukamoto)
  • Liver Injury: hepatotoxicity (inflammation, signal transduction, free radical/oxidative stress) and mitochondria (Coordinator, Neil Kaplowitz)
  • Repair, Regenerative Medicine, and Developmental Biology (Coordinator, Laurie DeLeve)

Over time, the major change has been the growth in Center’s research activities in steatohepatitis and in liver injury, justifying dividing these into two themes. At the same time the interest in normal liver cell biology and transport has declined and signal transduction research has shifted from normal physiology to liver injury. The Regulatory Biology theme has sharpened its focus to regeneration, repair and development biology.

Theme 1: Viral Hepatitis and Hepatocellular Carcinoma

This theme has been longstanding in our Center and is one of its major scientific strengths. 22 Center members are in this Theme. Dr. Ou is Theme Coordinator and represents the Theme at the Executive Committee. There are two subthemes which we refer to as Special Interest Groups (SIGs): viral hepatitis and hepatocellular carcinoma. Dr. Ou works on the molecular virology and pathogenesis HBV and HCV and their role in liver cancer development, reflecting the rationale for combining the two subthemes.

Theme 1: Viral Hepatitis and Hepatocellular Carcinoma
Coordinator: James Ou, PhD, Molec. Micro. & Immunol.
Special Interest Groups:
Viral Hepatitis: Hepatocellular Carcinoma:
Tse-Ling Fong, MD Medicine/GI/Liver Doug Feldman, PhDa Pathology
Saro Khemichian, MD Medicine/GI/Liver Wendong Huang, PhDa Biochem. & Molec. Biol.
Jeff Kahn, MD Medicine/GI/Liver Cheng Ji, PhDa Medicine/GI/Liver
Andrea Kovacs, MDa Pediatrics/Pathology Jeff Kahn, MD Medicine/GI/Liver
Keigo Machida, PhDa Molec. Micro. & Immunol. Amy Lee, PhDa Biochem. & Molec. Biol.
James Ou, PhDa Molec. Micro. & Immunol. Chengyu Liang, MD, PhDa Molec. Micro. & Immunol.
Takeshi Saito, MD, PhDa Med/ Molec. Micro. & Immunol. Shelly Lu, MDa Medicine/GI/Liver
Weiming Yuan, PhDa Med/ Molec. Micro. & Immunol. Keigo Machida, PhDa Molec. Micro. & Immunol.

a: Research support in Table A.1
b: co-investigator in Table A.1

Jose Mato, MDb Spain
James Ou, PhDa Molec. Micro. & Immunol.
Linda Sher, MD Surgery Hepat./Liver Trans.
Bangyan Stiles, PhDa Pharm. & Pharm. Sci.
Hide Tsukamoto, DVM, PhDa Pathology
Heping Yang, PhDb Medicine/GI/Liver
Shuping Zhong, PhD Biochem. & Molec. Biol.
Note: Pathologists, Govindarajan, and Kanel, support the activities of this theme.

The viral hepatitis SIG (8 members) consists of a molecular virology/pathogenesis group. Dr. Ou works on the life cycle of HBV and HCV as well as immunopathogenesis of viral-host interactions. Particularly noteworthy is the work of Ou in identifying the role of autophagy in viral replication. Joining Dr. Ou, are Machida, Saito, and Yuan who are working on the role of the innate immune system and evasion in hepatitis viral infection. In addition, a group of clinical investigators work on HCV infection and its treatment in special populations such as HIV co-infection and orthotopic liver transplantation and HBV in the large Asian population in Southern California. Members are Fong, Khemician, Kahn, Kovacs.

The hepatocellular carcinoma SIG (15 members) has grown considerably in the past five years and its major focus is on the role of liver diseases such as chronic viral hepatitis, steatohepatitis, and liver metabolism in the molecular pathogenesis of hepatocarcinogenesis and the regulation of liver cancer stem cells. Numerous collaborations exist between these investigators, which is reflected in joint publications and the group has been meeting on a regular basis along with USC oncologists in the Cancer Center to plan the submission of a SPOR grant on novel strategies in treatment and prevention of hepatocellular carcinoma.

Supporting the efforts of investigators in this Theme is the active participation and collaboration of liver pathologists Govindarajan and Kanel, who assist investigators in the interpretation of animal and human histopathology and the Liver Histology Core. In addition, the Tissue Repository run by Dr. Sher has provided normal and diseased liver and liver cancer specimens to many members of this Theme. A few of the major accomplishments of the investigators in this Theme are illustrated by the following recent publications, noted by the focus on liver disease (viral, alcohol, fatty liver, hepatic metabolism, signal transduction) in the pathogenesis of liver cancer and the activation of cancer stem cells. Current and former Center members are highlighted in bold.

  • Galicia VA, He L, Dang H, Kanel G, Vendryes C, French BA, Zeng N, Bayan JA, Ding W, Wang KS, French S, Birnbaum MJ, Rountree CB*, Stiles BL. Expansion of hepatic tumor progenitor cells in Pten-null mice requires liver injury and is reversed by loss of AKT2. Gastroenterology 139:2170-2182, 2010. This work demonstrates that liver carcinogenesis in Pten-null mice requires not only the transformation of tumor-initiating cells but selection pressure from hepatic injury and cell death, which activates these cells. (Rountree is a former member and P/F project holder).
  • Feldman DE, Chen C, Punj V, Tsukamoto H, Machida K. Pluripotency factor-mediated expression of the leptin receptor (OB-R) links obesity to oncogenesis through tumor-initiating stem cells. PNAS 109:829-834, 2012. This work identifies that the selective robust expression of OB-R is a characteristic feature of tumor-initiating stems and is mediated by transcription factors OCT4 and SOX2.
  • Yang H, Cho ME, Li TW, Peng H, Ko KS, Mato JM, Lu SC. MicroRNAs regulate methionine adenosyltransferase 1A expression in hepatocellular carcinoma. J. Clin Invest 123:285-298, 2013. This work shows that upregulation of miR-664, miR-485-3p, and miR-495 contribute to reducing MAT1expression in HCC and knockdown of these miRNAs reduces tumor growth, invasion and metastasis.
  • Chen CL, Tsukamoto H, Liu JC, Kashiwabara C, Feldman D, Sher L, Dooley S, French SW, Mishra L*, Petrovic L, Jeong JH, Machida K. Reciprocal regulation by TLR4 and TGF-β in tumor-initiating stem-like cells. J. Clin Invest 123:2832-2849, 2013. This work uses HCV transgenic mouse model and clinical specimens to demonstrate the signaling pathway that activates the TLR4/NANOG oncogenic pathway through suppression of cytostatic TGF-β signaling. *(Mishra is one of our Scientific Advisory Board Members).
  • Chen W, Tseng C, Pfaffenbach K, Kanel G, Lu B, Stiles B, Lee A. Liver-specific knockout of GRP94 in mice disrupts cell adhesion, activates liver progenitor cells, and accelerates liver tumorgenesis. Hepatology 59: 947-957, 2014. This study demonstrates that deletion of GRP94 along with PTEN accelerates liver carcinoma derived from progenitor cells.

Theme 2: Steatohepatitis and Fibrosis

This theme represents another area of major strength in the RCLD. 19 Center members work in this theme. An important component of this theme is the NIAAA supported Southern California Research Center for Alcoholic Liver and Pancreatic Disease and Cirrhosis. This Center has membership from UCLA, UC Irvine and UCSD and is based at the Keck School of Medicine of USC. The Alcohol Center Director, Hide Tsukamoto, is a member of the RCLD Executive Committee and Theme 2 Coordinator. Drs. Kaplowitz and Lu are members of the Executive Committee of the Alcohol Center. Both Centers work together closely in coordinating activities, minimizing overlap, providing Core facility access to USC faculty members, sharing a seminar series and insuring that support of P/F projects is not duplicated. The Alcohol Center provides two Core facilities on our campus: an Animal Model Core (intragastric alcohol fed rodents and combined intragastric alcohol/obesity model) and a Nonparenchymal Cell Core which provides stellate cells and Kupffer cells. These cores do not overlap those of the RCLD. Aside from the Alcohol Center cores, the P50 Center has individual research projects. At present project 1 (Fernandez-Checa and Kaplowitz) and project 3 (Machida and Tsukamoto) are the only components of the Alcohol Center listed in our research base Table A.1.

Theme 2: Steatohepatitis and Fibrosis
Coordinator: Hide Tsukamoto, DVM, PhD, Pathology
Special Interest Groups:
Alcoholic and nonalcoholic steatohepatitis: Animal/Cell Models: Alcoholic and nonalcoholic steatohepatitis:
Clinical Translational Research:
Doug Feldman, PhD Pathology Pinchas Cohen, MD Gerontology
Jose Fernandez-Checa, PhDa Spain John Donovan, MD Medicine/GI/Liver
Cheng Ji, PhDa Medicine/GI/Liver Neil Kaplowitz, MDa Medicine/GI/Liver
Neil Kaplowitz, MDa Medicine/GI/Liver Zhang-Xu Liu, PhDa Medicine/GI/Liver
Amy Lee, PhDa Biochem. & Molec. Biol. Shelly Lu, MDa Medicine/GI/Liver
Shelly Lu, MDa Medicine/GI/Liver Mazen Noureddin, MD Medicine/GI/Liver
Keigo Machida, PhDa Molec. Micro. & Immunol. Andrew Stolz, MDa Medicine/GI/Liver
Jose Mato, MDb Spain Fibrosis:
Takeshi Saito, MD, PhD Medicine/GI/Liver Kinji Asahina, PhDa Pathology
Michael Stallcup, PhDa Biochemistry Laurie DeLeve, MD, PhDa Medicine/GI/Liver
Bangyan Stiles, PhDa Pharm. & Pharm. Sci. Keigo Machida, PhDa Molec. Micro. & Immunol.
Tin Aung Than, MDb Medicine/GI/Liver Komal Ramani, PhDa Medicine/GI/Liver
Hide Tsukamoto, DVM, PhDa Pathology Anisa Shaker, MDa Medicine/GI/Liver
Sanda Win, MD, PhDb Medicine/GI/Liver Hide Tsukamoto, DVM, PhDa Pathology
Jun Xu, MD, PhDa Pathology Kasper Wang, MDa Pediatrics
Heping Yang, PhDb Medicine/GI/Liver Jun Xu, MD, PhDa Pathology
a: Research support in Table A.1
b: co-investigator in Table A.1
Note: Dr. Kanel and Govindarajan support and collaborate with these SIGs.

There are a number of investigators studying the molecular mechanisms of steatohepatitis with extensive collaborations so that among the 16 investigators in this SIG, all collaborate with at least one or more among them. Fernandez-Checa, Ji, Lee, Than, Win and Kaplowitz study various aspects of the role of ER stress in alcoholic and non-alcoholic liver injury and the interplay of ER stress and mitochondrial dysfunction. Lee and Stiles collaborate on the role of signal transduction in fatty liver disease and liver cancer. Feldman, Mato, Lu, Tomasi and Tsukamoto investigate the role of epigenetic dysregulation and Xu and Tsukamoto examine the synergy of alcohol and overfeeding and the development of an animal model of alcoholic hepatitis.

A group of investigators are conducting clinical research on the treatment of alcoholic hepatitis (U01) including Stolz, Liu, Donovan and Kaplowitz, Noureddin collaborates with Kaplowitz on fatty liver disease and risk of drug-induced liver injury, and with Cohen and Kaplowitz on the study of mitochondrial DNA encoded humanins as biomarkers of human NAFLD/NASH, with Lu on the role of S-adenosylmethionine in human non-alcoholic steatohepatitis. 7 Center members are listed in this SIG.

Another special interest group studies the pathogenesis of fibrosis with a particular focus on stellate cell biology. Among this group of 8 investigators, close collaborations exist between Asahina, Machida, Tsukamoto, Wang and Xu. DeLeve studies the interplay between sinusoidal endothelial cells and stellate cells in progression and regression of fibrosis and Shaker studies the regulation of mesenchymal cells in fibrosis in the gut. Ramani studies the role of dysregulation of the MAT genes in stellate cell pathobiology with the collaboration of Lu and Tsukamoto. Drs. Asahina and Wang collaborate on studies of the pathogenesis of biliary fibrosis in mouse and human biliary atresia and on the origins of Myofibroblasts; this somewhat overlaps with theme 4 regarding progenitor cells in liver disease.

The following publications highlight several of the most outstanding recent contributions of this Theme:

  • Zhu NL, Wang J, Tsukamoto H. The Necdin-Wnt pathway causes epigenetic peroxisome proliferator-activated receptor gamma repression in hepatic stellate cells. J Biol Chem 285:30463-71, 2010. The study discovered that silencing necdin reverted activated stellate cells to quiescence by suppressing Wnt leading to epigenetic derepression of PPARg.
  • Xie G, Wang X, Wang L, Wang L, Atkinson RD, Kanel GC, Gaarde WA, Deleve LD. Role of differentiation of liver sinusoidal endothelial cells in progression and regression of hepatic fibrosis in rats. Gastroenterology 142:918-927, 2012. This paper demonstrates that reversal of capillarization of SEC leads to quiescence of hepatic stellate cells and regression of fibrosis and that maintenance of differentiation of SEC prevents progression of fibrosis and cirrhosis.
  • Li Y, Wang J, Asahina K. Mesothelial cells give rise to hepatic stellate cells and myofibroblasts via mesothelial-mesenchymal transition in liver injury. PNAS 110:2324-2329, 2013. This study indicates that mesothelial cells participate in liver injury via differentiation to hepatic stellate cells and myofibroblasts; antagonism of TGF-β signaling suppresses transition of mesothelial cells to mesenchymal cells.
  • Ji C, Kaplowitz N, Lau MY, Kao E, Petrovic LM, Lee AS. Liver-specific loss of glucose-regulated protein 78 perturbs the unfolded protein response and exacerbates a spectrum of liver diseases in mice. Hepatology 54:229-239, 2011. Liver-specific loss Grp78/BiP leads to spontaneous steatosis, apoptosis, and exacerbates a spectrum of acute and chronic liver diseases through global perturbation of the unfolded protein response.
  • Mavila N, James D, Shivakumar P, Nguygen M, Utley S, Mak K, Wu A, Shou S, Wang L, Vendyres C, Graff M, Asahina K, Wang K. Expansion of prominin-1-expressing cells in association with fibrosis of biliary atresia. Hepatology 60: 941-953, 2014. Expansion of prominin-1 progenitor cells is linked to evolving fibrosis in both experimental mouse ad human biliary atresia.

Theme 3: Liver Injury

The Liver Injury Theme 3 ranks with Themes 1 and 2 as an area of exceptional expertise and accomplishment of the Center. Dr. Kaplowitz has assumed the role of Coordinator. Overall 19 Center members work in this Theme. This theme is bolstered by translational work on genetics, immunology and biomarkers of DILI through the participation of Dr. Stolz, Liu and Kaplowitz in the NIDDK sponsored DILIN and by the new initiative supported by university funds to establish a Free Radical Institute lead by four Center Members, Drs. Cadenas, Davies, Kaplowitz and Tower. This group holds weekly seminars which are podcast on the Health Sciences and University Park Campuses and all-day retreats which has triggered collaborations in metabolic liver disease and mitochondrial pathobiology. USC is home to a group of exceptionally accomplished experts in mitochondrial biology including Kaplowitz, Cadenas, Cohen, Davies, Fernandez- Checa, and Tower, all of whom collaborate on mitochondrial bioenergetics and signal transduction pathways that interplay with liver mitochondria and their quality control in health and disease. In addition, a group of young and established investigators collaborate with senior faculty and participate in mitochondrial studies including Feldman (mitochondrial UPR), Machida (metabolic reprogramming in liver cancer stem cells), Stiles (AKT regulation of biogenesis and bioenergetics), Than (mitochondrial biogenesis), Win (JNK interaction with mitochondria), Xu (metabolic reprogramming of macrophages in alcoholic liver disease), and Zandi (mitochondrial transmembrane tumor suppressor 1). 11 Center members work in this SIG.

Theme 3: Liver injury – Hepatotoxicity (Inflammation, Signal Transduction, Free Radical/Oxidative Stress) and Mitochondrial Pathobiology
Coordinator: Neil Kaplowitz, MD, Medicine/GI/Liver
Special Interest Groups:
Hepatotoxicity and Inflammation: Mitochondrial Pathobiology in Liver Disease:
Lily Dara, MD Medicine/GI/Liver Enrique Cadenas, PhD Pharm. & Pharm. Sci.
Laurie DeLeve, MD, PhDa Medicine/GI/Liver Pinchas Cohen, MD Gerontology
Jose Fernandez-Checa, PhDa Spain Kelvin JA Davies, PhDa Bio-Gerentology
Cheng Ji, PhDa Medicine/GI/Liver Doug Feldman, PhDa Pathology
Neil Kaplowitz, MDa Medicine/GI/Liver Jose Fernandez-Checa, PhDa Spain
Amy Lee, PhDa Biochem. & Molec. Biol. Neil Kaplowitz, MDa Medicine/GI/Liver
Zhang-Xu Liu, PhDa Medicine/GI/Liver Bangyan Stiles, PhDa Pharm. & Pharm. Sci.
Shelly Lu, MDa Medicine/GI/Liver Tin Aung Than, MDb Pathology
Andrew Stolz, MDa Medicine/GI/Liver John Tower, PhDa Medicine/GI/Liver
Tin Aung Than, MDb Pharm. & Pharm. Sci. Sanda Win, MD, PhDb Molec. Micro. & Immunol.
Sanda Win, MD, PhDb Medicine/GI/Liver Ebrahim Zandi, PhDa Molec. Micro. & Immunol.
Heping Yang, PhDb Medicine/GI/Liver
a: Research support in table A.1
b: co-investigator in Table A.1
Note: Dr. Kanel and Govindarajan support this Theme with pathology expertise and collaboration.

Another closely related SIG focuses on the mechanisms of experimental hepatotoxicity including oxidative stress, signal transduction and the immune system. 12 members work in this SIG. Fernandez-Checa and Kaplowitz study the regulation of mitochondrial GSH and along with Than and Win study the interplay of ER stress and mitochondria. Ji, Lee and Kaplowitz examine ER stress in liver injury models, Kaplowitz, and Dara study signal transduction pathways in liver cell death, Dara, Kaplowitz and DeLeve study cell death pathways in nonparenchymal cells and the relevance to DILI. Liu, Kaplowitz and Stolz study the role of innate and adaptive immune systems in animal models and humans with DILI, and Yang and Lu study the regulation of GSH synthesis in cholestatic liver injury.

Several important recent publications from investigators in this theme are highlighted.

  • Win S, Than TA, Han D, Petrovic LM, Kaplowitz N. c-Jun N-terminal kinase (JNK)-dependent acute liver injury from acetaminophen or tumor necrosis factor (TNF) requires mitochondrial Sab protein expression in mice. J. Biol. Chem. 286:35071-35078, 2011. This landmark study identified that in various cell death scenarios in liver injury, JNK translocation to mitochondria plays a key role and is determined by JNK binding to Sab, an outer membrane protein, leading to impaired mitochondrial function, ROS production, and necrosis or apoptosis.
  • Than TA, Lou H, Ji C, Win S, Kaplowitz N. Role of cAMP-responsive element-binding protein (CREB)-regulated transcription coactivator 3 (CRTC3) in the initiation of mitochondrial biogenesis and stress response in liver cells. J. Biol. Chem 286:22047-22054, 2011. This paper describes the discovery of a transcriptional co-activator, CRTC3, which regulates the CREB dependent transcription of PGC1a, the master regulator of mitochondria biogenesis and that the other CREB co-activator, CRTC2, is dispensable in mitochondrial biogenesis in response to mitochondrial-specific stress whereas both CRTC 2 and 3 are interchangeable in regulating mitochondrial biogenesis in response to metabolic stress (eg. Fasting).
  • Li Y, He L, Zeng N, Sahu D, Cadenas E, Shearn C, Li W, Stiles BL. Phosphatase and Tensin Homolog Deleted on chromosome 10 (PTEN) signaling regulates mitochondrial biogenesis and respiration via estrogen-related receptor α (ERRα). J. Biol. Chem. 288:25007-25024, 2013. This paper demonstrates that PI3K/AKT regulates mitochondrial biogenesis through expression of ERRa by CREB phosphorylation independent of PKA signaling.
  • Win S, Than T, Fernandez-Checa J, Kaplowitz N. JNK interaction with Sab inhibition of mitochondrial respiration and cell death. Cell Death Dis. 5, e989, 2014. This study demonstrates that chemical induced ER stress causes mitochondrial dysfunction, increased ROS, and apoptosis, all of which are dependent on the interaction of P-JNK with mitochondrial Sab.

Theme 4: Repair, Regenerative Medicine and Developmental Biology

This Theme is an emerging one in the Center with 13 members. (10 are new since 2008). Dr. DeLeve is Coordinator of this Theme which consists of two SIGs, one focused on liver studies and one focused on gut studies. Drs. Asahina, Wang, and Tsukamoto collaborate to study developmental biology of hepatic mesenchymal cells, Drs. Crump and Wang collaborate to study developmental biology of cholangiocytes and the pathogenesis of Alagille’s syndrome and biliary atresia. Also, Dr. Wang is the site PI for U01 for the study of Childhood Cholestatic Liver Disease. Dr. Miki studies the use of placental stem cells for the development of hepatocytes and collaborates with Dr. Kaplowitz in phenotyping iPS derived liver cells. Dr. DeLeve studies the role of bone marrow derived endothelial progenitor cells in liver regeneration. Drs. Tsukamoto and Asahina study the role of stellate cells in liver regeneration.

Theme 4: Repair, Regenerative Medicine and Developmental Biology (RRMD)
Coordinator: Laurie DeLeve, MD, PhD, Medicine/GI/Liver
Special Interest Groups:
Liver RRMD: Gut Injury and RRMD:
Kinji Asahinaa Pathology William DePaolo, PhDa Molec. Micro. & Immunol.
Gage Crump, PhDa Cell and Neurobiology Mark Frey, MDa Pediatrics
Laurie DeLeve, MD, PhDa Medicine/GI/Liver Tracy Grikscheit, MDa Pediatric Surgery
Toshio Miki, MD, PhDa Biochem. & Molec. Biol. Andre Ouellette, PhDa Pathology & Lab. Med.
Hide Tsukamoto, DVM, PhDa Pathology Brent Polk, MDa Pediatrics
Kaspar Wang, MDa Pediatric Surgery Ling Shao, MDa Medicine/GI/Liver
Michael Stallcup, PhDa Biochem. & Molec. Biol. Anisa Shaker, MDa Medicine/GI/Liver
a: Research support in Table A.1
A gut injury, repair and developmental biology SIG consists of 7 members, 6 of whom are new members. Although gut disease is not the major focus of our Center, the investigators in this group share many common interests and scientific objectives with the liver investigators studying similar mechanisms of injury, repair, fibrosis, and regeneration. We strongly believe that the collaboration of liver researchers and this group is of great mutual benefit. Furthermore, the career development of young investigators such as Frey, DePaolo, Shaker and Shao in digestive disease research is markedly enhanced by the mentoring, enrichment, access to Core facilities and collaboration of the Liver Center and would not be possible without this. Drs. Frey and Polk collaborate on cell death mechanisms in the intestinal epithelium, Drs. DePaolo and Ouellette examine inflammation and defense in the intestines and Dr. Shaker focuses on injury and repair in the small intestine and esophagus and the role of bone marrow derived mesenchymal progenitor cells. Dr. Polk is mentor of Drs. Shaker and Shao’s K08 awards and Dr. Ouelette, DeLeve and Kaplowitz serve on their mentoring committees. Drs. DePaolo and Shaker held P/F project awards from the Center. The gut group meets regularly and has a monthly seminar/research-in-progress meeting. Dr. Grikscheit, a former P/F project holder is studying tissue-engineered small intestine and also participates in intellectual exchange with other members of this SIG and collaborates with Dr. Wang (liver organoid development) and Dr. Polk. Dr. Polk represents this SIG at the Executive Committee.

We list a few notable publications highlighting recent accomplishments of investigators in this Theme:

  • Wang L, Wang X, Xie G, Wang L, Hill CK, DeLeve LD. Liver sinusoidal endothelial cell progenitor cells promote liver regeneration in rats. J. Clin. Invest. 122: 1567-1573, 2012. This seminal paper demonstrates that LSEC progenitor cells are present in liver and bone marrow and recruitment of bone marrow LSEC progenitors is necessary for normal liver regeneration.
  • Zhu NL, Asahina K, Wang J, Ueno A, Lazaro R, Miyaoka Y, Miyajima A, Tsukamoto H. Hepatic stellate cell-derived delta-like homolog 1 (DLK1) protein in liver regeneration. J. Biol. Chem. 287: 10355-10367, 2012. This paper demonstrates that DLK-1, an EFG family protein, is induced in hepatic stellates during liver regeneration and supports early hepatocyte proliferation via Wnt pathway.
  • Lua I, James D, Wang J, Wang K, Asahina K. Mesodermal mesenchymal cells give rise to myofibroblasts, but not epithelial cells, in mouse liver injury. Hepatology 60: 311-322, 2014. Cell lineage tracing demonstrated that mesodermal mesenchymal cells are the major source of myofibroblasts but do not differentiate into epithelial cells types.

Special Expertise in the Center

In addition to the Themes, several members provide unique expertise to the Center. Drs. Shen and MacKay, pharmaceutical scientists, develop novel methods for targeting peptide therapeutics to the liver which has led to collaborations with Drs. DeLeve, Ou and Hamm-Alvarez. Dr. Crump provides a zebra fish facility which has led to collaboration with Dr. Wang on Alagille’s model. Dr. Tower provides an opportunity for collaboration on studies in the Drosophilia model and has ongoing collaborations with Drs. Cohen, Davies and Kaplowitz. Dr. Stallcup is an international authority on regulation of transcription and provides expertise and advice on studies involving co-activators and co-repressors; his Center-related research involves the regulation of genes of hepatic lipid synthesis.

Research Base

The RCLD has been funded since 1995. During the first decade (cycles 1 and 2) the membership and research base funding nearly doubled in parallel with growth of the overall NIH budget. During the past decade (cycles 3 and 4) we have experienced remarkable stability in size of membership and research base funding despite two major factors working against it: a) a more bleak funding environment with lower pay lines as well as budget cuts of funded grants, b) turnover of faculty at USC (see below). Despite these factors our membership is strong and our funding base has remained very stable. Tables 1 (membership roster, listed under Organization) and Tables 2 and 3 (below) show a comparison of membership, overall funding, and sources in the past three cycles. There has been a modest decrease in the NIDDK component of the research base funding, which is balanced by equivalent growth from combined support from NIAAA and the California Institute for Regenerative Medicine. We believe this should be viewed as a positive in that our objective is to enhance research in liver and digestive diseases and the small shift reflects our ability to compete and capture support from as many sources as possible in pursuit of the Center’s mission. Furthermore, NIDDK remains the single largest source of our research base. The next largest is NIAAA: all of that support is directed to liver disease and much of it relates to mechanisms of steatohepatitis and fibrosis, rather than specifically to alcoholic liver disease.

Table 2: Changes in Research Base

2003** 2008 2013 2014
Center Members* 58 63 57 58
Funded Members –
included in Table A.1
32 35 37 58
Peer Reviewed –
Research Base Grants
57 58 57 56
NIDDK-Funded Base
(direct $ millions)
$3.45 $3.55 $3.05 $3.07
Total Base
(Direct Costs)
$10.7 $10.1 $10.5 $10.9
% NIDDK 32.1 35.3 29.1 28.2
*Formerly members and affiliated members. ** Application date

Table 3: Sources of Research Base Funding and Comparison from 2003-2013

2003 2008 2013 2014
NIDDK 32.1% 35.3% 29.1% 28.2%
NIAAA 12.0% 18.0% 21.7% 19.0%
NCI 24.7% 15.4% 13.9% 15.1%
NCI (others) 28.9% 20.4% 20.7% 18.5%
(CIRM etc.)
2.4% 11.5% 14.5% 19.2%
Total $ $10,765,977 $10,107,730 $10,500,253 $10,869,394
All told, 19 of 41 members and 12 of 22 affiliated members from 2008 roster are no longer listed in our Center.  Joining the 32 remaining individuals from 2008 (original members and affiliated, now all members), there are 26 new members who joined since 2008 (resulting in the current total of 58 members). Nearly all are new faculty recruits to the University since 2008 (Table 4).

Table 4: RCLD New Members since 2008+

Pinchas Cohen, MD  (USC Gerontology School)* Komal Ramani, PhD (Liver-Med.)
Gage Crump, PhD (Cell Biology) * Takeshi Saito, MD, PhD (Med. Mol. Microbiol. Immunol.)*
Lily Dara, MD (Liver/Med.) Ling Shao, M.D., Ph.D. (GI/Liver – Med.) *
William DePaolo, PhD (Molec. Microbiol. Immunol.)* Anisa Shaker, MD (GI-Medicine) *
Douglas Feldman, PhD (Pathology) Maria Lauda Tomasi, PhD (Liver-Med.)*
Mark Frey, MD (Pediatrics)* John Tower, Ph.D (Biological Sciences)*
Jeff Kahn, MD (Transplant Hepatol. – Med.) Sanda Win, MD, PhD (Liver-Med.)
Saro Khemichian, MD (Transplant Hepatol. – Med.) Weiming Yuan, PhD (Mol. Microbiol. Immunol.)*
Andrea Kovacs, MD (Ped./Pathol.)* Jun Xu, MD, PhD (Pathology)*
Chengyu Liang, MD, PhD (Molec. Microbiol. Immunol.)* Shuping Zhong, PhD (Biochem./Mol. Biol.)
Andrew MacKay, Ph.D. (Pharmacol) + Six Departments (5 in GI/Liver – Dept. Med.). 18 are junior faculty level and 7 are at Assoc. or Prof. level including Cohen, Crump, Kahn, Kovacs, Ouellette, Polk, Zhong.
*Independent support in Research Base (17/25)
Toshio Miki, MD, PhD (Biochem./Mol. Biol.)*
Mazen Noureddin, MD (Hepatol.-Med.)
Andre Ouellette, PhD (Pathol.)*
Brent Polk, MD (Pediatrics)*
Center Members represent faculty of 9 different departments: 21 members have primary appointments in the Department of Medicine (all in the Division of Gastrointestinal and Liver Disease), 8 members are in the Pathology Department, 5 are from the Department of Molecular Microbiology and Immunology, 5 are in the Department of Biochemistry and Molecular Biology, 3 are in Surgery Department, 3 from the Pediatrics Department, and 5 in Pharmacology (School of Pharmacy) and 4 are in Stem Cell Biology.  USC Dornsife College and School of Gerontology contribute 3 members. Of the 58 members, 44 are located on the Health Science campus, 4 are based at USC Children’s Hospital of Los Angeles, 4 are based at Cedars-Sinai, 1 at City of Hope and 2 are from Spain (one with a summer appointment).

Current DD-Related Research Grant Support

Principal Investigator    
[MPI or Co-Investigator]
Supporting Organization/ Grant Number Title Project
Direct Costs
Last Name, First Name Complete title as shown on the grant Direct Cost $US
Ashahina, Kinji NIH/R01AA020753 Contribution of the mesothelium to alcohol-induced liver fibrosis. 09/01/2011 – 07/31/2016 206,125
Wright Foundation Role of the hippo transducer TAZ in mesothelial-mesenchymal transition. 07/08/2014 – 07/07/2015 50,000
Cohen, Pinchas NIH/R01GM090311 Novel mitochondrially derived peptides and their role in health and disease. 10/01/2009 – 09/31/2015 390,459
NIH/R01ES0280812 Plasma mitochondrial peptide assays as biomarkers of environmental toxin exposure. 10/01/2011 – 09/30/2016 222,750
Crump, Gage March of Dimes Role of the alagille syndrome gene JAGGED1 in dorsal-ventral patterning of the vertebrate face. 06/01/2013 – 05/31/2016 110,000
Davies, Kelvin J.A. [Tower, John] NIH/R01ES003598 Oxygen radical toxicity & protein degradation. 05/14/2013 – 07/29/2018 225,000
DeLeve, Laurie NIH/R01DK046357 Liver sinusoidal endothelial cells progenitor cells. 04/01/2013 – 03/31/2018 217,500
NIH/R01DK100580 Liver sinusoidal endothelial cells and fibrosis. 08/01/2014 – 07/31/2018 217,500
DePaolo, William NIH/R21RCA182595 The role of TLR1 in colorectal cancer. 08/01/2014 – 07/31/2019 130,500
USC Rose Hills foundation Manipulation of the microbiome to treat colorectal cancer. 07/01/2014 – 06/30/2015 75,000
NIH/R03DK097442 The impact of TLR1 on dysbiosis and intestinal inflammation. 01/01/20/13 – 12/31/2014 50,000
Fernandez-Checa, Jose  [Kaplowitz, N.] NIH/P50AA119999 Project 1 Mechanisms and impact of Star activation in ALD. 01/01/2009 – 12/31/2018 74,112
Frey, Mark NIH/R01DK095004 Regulation of colon epithelial cell survival by NRG4-ERBB4 signaling. 07/01/2013 – 05/31/2018 217,500
Grikscheit, Tracy CIRM/RN3-06425 The generation and expansion of tissue-engineered small intestine from human stem/progenitor cells; a preclinical study of functional translation. 01/01/2014 – 12/31/2018 400,000
Huang, Wendong NIH/R01CA139158 Investigation of the role of nuclear receptor FXR in hepatocellular carcinoma. 01/25/2011 – 12/31/2015 195,050
Ji, Cheng NIH/R01AA018612 no cost ext. Effect of HIV protease inhibitor on alcohol induced ER stress and liver injury. 04/01/2010 – 03/31/2015 212,305
Kaplowitz, Neil     [Than, A.]  [Win, S.] NIH/R01DK067215 Cellular mechanisms of hepatotoxicity. 04/01/2004 – 03/31/2015 217,500
[Ji, Cheng] NIH/R01AA014428 Homocysteine, ER stress and alcoholic liver injury. 04/01/2004 – 03/31/2015 221,436
Kovacs, Andrea NIH/R56AI052065 HCV and HIV progression in women on HAART. 06/01/2002 – 05/31/2015 470,391
Lee, Amy NIH/R01CA027607 Stress induction of glucose regulated protein GRP78/BiP. 04/01/1980 – 03/31/2017 280,069
NIH/R01CA027607 Stress induction of glucose regulated protein GRP78/BiP. (Administrative supplement) 06/01/2013 – 03/31/2015 44,532
NIH/R21CA179273 Targeting cell surface GRP78 as a novel therapy for pancreatic cancer. 06/01/2014 – 05/31/2016 130,500
Liang, Chengyu NIH/R01CA140964 Role of UVRAG-mediated autophagy in tumor suppression. 09/21/2009 – 07/31/2015 170,279
Liu, Zhang-Xu [Kaplowitz, Neil] NIH/U01AA021857 Immunity in alcoholic hepatitis. 09/01/2013 – 08/31/2018 174,601
Lu, Shelly NIH/R01AT001576 Role of SAMe in pathogenesis and treatment of non-alcoholic fatty liver disease. 09/20/2002 – 06/30/2019 205,939
[Yang, Heping] [Mato, Jose] NIH/R01DK051719 Regulation and functions of methionine adenosyltransferase genes in liver. 04/01/2006 – 06/30/2015 213,506
[Yang, Heping] NIH/R01DK092407 Dysregulation of GSH synthesis during liver injury and fibrosis. 04/01/2012 – 03/31/2017 195,750
NIH/R01CA172086 Prohibitin 1 in liver injury and cancer. 01/10/2014 – 12/31/2018 213,556
Machida, Kiego NIH/R01AA018857 Nanog-positive cancer stem cells in liver oncogenesis by alcohol and HCV. 09/15/2009 – 08/21/2015 210,182
ACS/RSGMPC122545 Nanog-mediated oncogenic signal and tumor stem cells in HCV carcinogenesis. 07/01/2012 – 06/30/2016 150,000
MacKay, Andrew Stop Cancer Foundation Genetically engineered nanoparticles for cancer imaging and drug delivery. 03/01/2011 – 02/25/2015 150,000
Miki, Toshio CIRM Generation of hepatic cell from placental stem cell for congenital metabolic disorders 10/01/2012 – 09/30/2015 399,984
Ou, James NIH/R01DK094652 Hepatitis C virus and autophagic response. 09/21/2011 – 08/31/2016 209,888
NIH/R0DK1100257 HBV replication and persistence in mouse models 08/01/2013 – 05/31/2017 217,500
NIH/R01CA177337 HBV replication and carcinogenesis. 09/01/2013 – 08/31/2016 121,921
Ouelette, Andre NIH/R21AI105057 Innate enteric immunity during induced paneth cell deficiency. 08/15/2013 – 07/31/2015 150,000
Polk, Brent (David) NIH/R01DK056008 Cytokine regulation of intestinal epithelial restitution. 08/01/2009 – 07/31/2017 217,500
CCFA Protective effects of epidermal growth factor receptor (EGFR) signaling in colitis-associated cancer. 07/01/2012 – 06/30/2015 105,300
Saito, Takeshi NIH/R21AA022751 Retinoid regulation of hepatic innate immunity. 08/20/2014 – 07/31/2015 143,750
Shaker, Anisa AGA no cost ext. Innate immune cell modulation of gut microbiota in colitis and colitis associated cancer. 12/01/2010 – 06/30/2015 75,000
Wright no cost ext. Esophageal myofibroblasts participate in the mucosal injury and repair response. 07/01/2013 – 06/30/2015 50,000
NIH/K08CA153036 Epimorphon deletion alters stem cell niche myofibroblast secretion. 07/01/2011 – 01/31/2017 134,707
Shao, Ling NIH/K08DK100462 The ubiquitin editing enzyme A20 preserves intestinal epithelial cell homeostasis. 09/03/2014 – 07/31/2019 142,990
Shen, Wei-Chiang NIH/R01GM063647 Transferrin conjugates for oral peptide drug delivery. 04/01/2002 – 04/30/2015 174,000
Stallcup, Michael NIH/R37DK055274 Protein methytransferase as transcriptional coregulators. 01/15/1999 – 12/31/2017 331,734
Stiles, Bangyan NIH/R01DK084241 The mechanism of beta-cell regeneration. 07/01/2010 – 06/30/2015 173,250
NIH/R01CA108614 Novel targets that are deregulated by loss of PTEN. 04/01/2014 – 03/31/2017 21,255
Stolz, Andrew NIH/U01DK083020 USC-UCLA drug-induced liver injury (DILI) clinical center. 09/30/2008 – 06/30/2018 235,172
NIH/U01AA021886 SCAHC clinical trial in patients with alcoholic hepatitis. 09/20/2013 – 08/31/2019 225,317
Tomasi, Maria Lauda NIH/K01AA022372 Role of Sumoylation in alcoholic liver disease. 09/30/2013 – 08/31/2018 145,112
Tower, John NIH/R01AG011833 no cost ext Aging specific gene expression in drosophila. 03/01/2009 – 02/28/2015 157,369
Tsukamoto, Hide NIH/U01AA018663 Epigenetic regulation of alcoholic liver fibrosis. 09/01/2010 – 08/30/2015 254,013
VA/BX001991 Molecular mechanisms of stellate cell activation in liver fibrosis. 10/04/2004 – 09/30/2017 150,000
VA/Senior Research Career Sci. Award Molecular mechanisms of stellate cell activation in liver fibrosis. 04/01/2004 – 03/31/2008 155,000
NIH/U01AA018663 Epigenetic regulation of alcoholic liver fibrosis. 09/01/2010 – 08/30/2015 254,013
Toray Industries, Inc. Therapeutic actions and mechanisms of baicalein toward liver tumor initiating cells. 07/01/2014 – 06/30/2017 219,915
NIH/U01AA022614 The role of IL-17 in alcoholic liver disease and cancer 09/01/2014 – 06/30/2019 45,000
NIH/R01AA021751 The dynamics and mechanisms of autophagy in ethanol-induces liver pathogenesis. 08/15/2013 – 07/31/2018 49,350
Wang, Kaspar NIH/U01KD084538 Continuation of the CHLA’s liver research center. 09/10/2009 – 05/31/2019 212,000
Xu, Jun NIH/K01AA020524 Notch signaling in NOS2 activation and steatohepatitis by obesity and alcohol. 08/20/2011 – 07/31/2016 99,768
Yuan, Weiming NIH/R01AI091987 Herpes simplex virus-1 evasion of CD10 antigen presentation pathway. 05/01/2012 – 04/30/2017 250,000
Zandi, Ebrahim Jean Perkins Foundation The role of a novel mitochondrial protein in cancer. 12/01/2007 – 12/01/2015 300,000