FINAL 2016 NEWSLETTER - PAGES 1 and...

The Southern California ResearchCenter for ALPD and CirrhosisKeck School of Medicine of theUniversity of Southern California1333 San Pablo Street, MMR 4th FloorLos Angeles, CA 90033-9141

www.usc.edu/alpd

PHOTO FROM THE CENTER’S 17TH ANNUAL SYMPOSIUM ON DECEMBER 4, 2015

TODAY THE SOUTHERN CALIFORNIA RESEARCHCENTER FOR ALPD AND CIRRHOSIS

CONTACTSHidekazu Tsukamoto

Director

[email protected]

323-442-5107

Asma Deras

Business/Budget [email protected]

Fax: 323-442-3126

www.usc.edu/alpd

Program Administrator (2015-2016) and Newsletter Editor:Sean Kohlmeier

Our Center which is supported by a NIAAA P50 grant is a multi-component program encompassing Administrative Core, Animal Core, Morphology Corefour distinct Research Projects, and a Pilot Project program. In its 18th year,the Center has begun its self-evaluation. To perform this task, the productivity of each Center component must �rst be carefully evaluated. To this end, the Center’s External Advisory Board has been asked to “peer-review” the data generated by each component during the past four years . The independent and critical review provided by the External Advisory Board and its valuable feedback, are essential for the Center’s self-assessment and its future programmatic devolopment. The following summarizes the overall state of the Center and activities of AnimalCore which truly is the center’s epicenter unifying the cener members, catalyzing collaborations, and serving as an pivotal national resource for investigators in the �eld of alcoholic liver and pancreatic diseases, cirrhosis, liver and pancreatic cancer across the nation.

EVALUATION OF THE CENTER’S COMPONENTS BY THE EXTERNAL ADVISORY BOARD

FALL 2016The Center is supported by grants

from the National Institute on Alcohol Abuse and Alcoholism: P50 AA011999,

R24 AA012885 and R13 AA020691.

INSIDE THIS ISSUE

1 Evaluation of Center’s Components

2 Spotlight on Dr. Hamid Said

3 The Integrative Liver Cell Core Renwal

4 New Animal Core Model: Patient-Derived Xenograft

4 11th International Symposium on ALPD/C

4 Lee Summer ResearchFellowship Program

5 Recent Grants andPublications (2016)by Center Members

Who are the Center’sExternal AdvisoryBoard Members?

Dr. Ramon Bataller

Dr. Bin Gao

Dr. Vijay Shah

Dr. Laura Nagy

Dr. Nicholas Davidson

Dr. Gyongyi Szabo

Dr. Ashok Saluja

Numbers at Glance for 2013-2016:

Center as a whole:

• 64 center members from 59 in 2013• $14.1M research base (direct costs) of which $7M from NIAAA• 185 publications of which 43% collaborative papers

The Animal Core supported in the last 4 years:

• 2486 models produced based on 19 di�erent model versions• 22 center members • 56 publications by center members • 35 collaborative papers • 25 grants acquired/applied by the center members • 13 non-center investigators • 4 publications by non-center members• 15 grants acquired/applied by non-center investigators• 430 samples shared by 16 non-center investigators via Tissur Sharing Program

Pilot Project Program OutcomeA total of 16 Pilot Projects were funded by the Center between 2013 and 2016, with $319,000 in funds distributed for the program. The outcomes during this grant cycle are notable, with the following NIH grants acquired by Pilot Project alumni: K01AA020524 (PI: Jun Xu), R21AA022751 (PI: Takeshi Saito),R01DK101773 (PI: Takeshi Saito), R21AA023574 (PI: Akiko Eguchi),K08AA025112 (PI: Keane Lai - pending).

[CONTINUED ON NEXT PAGE]

Hiekazu TsukamotoCenter Director

www.usc.edu/alpd 5

HAMID SAID, Center Associate Director for Education and Training, is a full Professor (above-scale)in the Departments of Medicine and Physiology/Biophysics of the University of California School of Medicine at Irvine. He holds a joint appointment with the Long Beach VA Medical Center as a Senior Research Career Scientist. Dr. Said did his postdoctoral research fellowship at the Scripps Clinic and Research Foundation in La Jolla, CA. In 1982 he joined the University of California School of Medicine at Irvine as a junior faculty. In 1984 he was recruited to the Vanderbilt Medical School in Nashville, TN, as an Assistant Professor, and returned to UCI in 1988 as an Associate Professor. He was promoted to a full Professor in 1994, and granted a tenure status in 2001.

The research of Dr. Said over the past thirty years has focused on studying the physiology and pathophysiology of water-soluble vitamin absorption/transport in organs of the digestive system. He has published seminal work in these areas and was the �rst to identify the existence of speci�c transport systems for many of these vitamins in a variety of epithelia, characterize their transcriptional

and post transcriptional regulation, and study the cell biology of the membrane transporters involved (i. e., membrane targeting/intracellular tra�cking). An example of the latter is his identi�cation of the existence of e�cient and speci�c carrier-mediated mechanisms for the absorption of many of the microbiota-generated water-soluble vitamins (e. g., biotin, thiamin, thiamin pyrophos-phate, ribo�avin, niacin, pyridoxine, and folate) in the human colon. Dr. Said has also been investigating the e�ect of exogenous/environmental factors that interfere with the absorption/transport of these essential micronutrients leading to de�ciency and sub-optimal levels, with a special focus on the e�ects of chronic alcohol use and chronic exposure to components of cigarette smoke. His studies have covered the entire spectrum of biological complexity from the whole (integrative) organism level, to intact tissues, isolated/cultured cells, sub-cellular organelle/components, to the molecular level, and have utilized state-of-the-art cellular, molecular, genetic and imaging approaches.


SPOTLIGHT ON: HAMID SAID, Ph.D., Pharm.D.

[CONTINUED FROM PREVIOUS PAGE - PILOT PROJECT OUTCOMES]

There were a total of 26 publications in the period from 2013-2016 by Pilot Project PI’s. Other career development outcomes of these PI’s include the following:A) Promotions 1) Shabnam Shalapour - From Project Scientist to Asst. Adjunct Professor

16 non-center investigators supported via

Tissue Sharing

19 grants acquired or applied

for by non-center investigators

supported by theAnimal Core

2013 - 201613 non-center investigators supported by

the Animal Core

www.usc.edu/alpd 2

Dr. Said’s research has been indepen-dently funded by the NIH/VA for over a quarter of a century. He currently holds the prestigious NIH MERIT Award for Consistent & Excellent Contributions to Scienti�c Knowledge (2009-2019), as well as the prestigious Senior Research Career Scientist Award from the DVA (1996-2022). He has received numerous awards, including the Horace W. Davenport Distinguished Award - the most prestigious award of the AmericanPhysiological Society (GI) (2012) in recognition of his distinguished lifetime achievement in GI and liver physiology.

AlcoholInhibits

Intestinal absorption

of WSV

Pancreatic uptakeof WSV

Liver uptakeof WSV

Vitamin deficiency/sub-optimal levels

Clinical Symptoms(anemia, neurological

disorder, cardiovascular disease, etc.)

Effect of chronic alcohol intake on physiology of water-soluble vitamins (WSV), and its consequence

1. Uthaya Kum

ar D. B., C

hen C.L., Liu J.C

., Feldman D

., Sher L.S., French S., DiN

orcia J., French S.W

., Naini B.V., Junrungsee S., Agopian V.G

., Zarrinpar A., Machida K. TLR

4 Signaling via N

ANO

G C

ooperates With STAT3 to Activate Tw

ist1 and Promote Form

ation of Tum

or-initiating Stem

-like C

ells in

Livers of

Mice.

2016 M

ar;150(3):707-19. doi:

10.1053/j.gastro.2015.11.002. Epub 2015 Nov 12. PM

ID: 26582088. PM

CID

: PMC

4766021. 2.

Mandrekar

P, Bataller

R,

Tsukamoto

H,

Gao

B. Alcoholic

hepatitis: Translational

approaches to develop targeted therapies. Hepatology. 2016 M

ar 3. doi: 10.1002/hep.28530. [Epub ahead of print] PM

ID: 26940353. PM

CID

: PMC

5010788. 3. M

ukherjee R, M

areninova OA, O

dinokova IV, Huang W

, Murphy J, C

hvanov M, Javed M

A, W

en L, Booth DM

, Cane M

C, Aw

ais M, G

avillet B, Pruss RM

, Schaller S, Molkentin JD

, Tepikin AV, Petersen O

H, Pandol SJ, G

ukovsky I, Criddle D

N, G

ukovskaya AS, Sutton R;

NIH

R

Pancreas Biom

edical R

esearch U

nit.Mechanism

of

mitochondrial

permeability

transition pore induction and damage in the pancreas: inhibition prevents acute pancreatitis

by protecting production of ATP. Gut. 2016 Aug;65(8):1333-46. doi: 10.1136/gutjnl-2014-

308553. Epub 2015 Jun 12. PMID

: 26071131. PMC

ID: P

MC

4920725. 4. Avila D

V, Barker DF, Zhang J, M

cClain C

J, Barve S, Gobejishvili L. D

ysregulation of hepatic cAM

P levels via altered Pde4b expression plays a critical role in alcohol-induced steatosis. J Pathol. 2016 Jun 11. doi: 10.1002/path.4760. [Epub ahead of print] PM

ID:

27287961. PMC

ID: PM

C4993672.

5. Chen C

L, Uthaya Kum

ar DB, Punj V, X

u J, Sher L, Tahara SM, H

ess S, Machida K.

NAN

OG

Metabolically R

eprograms Tum

or-Initiating Stem-like C

ells through Tumorigenic

Changes in O

xidative Phosphorylation and Fatty Acid Metabolism

. Cell M

etab. 2016 Jan 12;23(1):206-19. doi: 10.1016/j.cm

et.2015.12.004. Epub 2015 Dec 24. PM

ID: 26724859.

PMC

ID: P

MC

4715587. 6. Li Y, Lua I, French SW

, Asahina K. Role of TG

F-β signaling in differentiation of mesothelial

cells to vitamin A-poor hepatic stellate cells in liver fibrosis. Am

J Physiol Gastrointest Liver

Physiol. 2016 Feb 15;310(4):G262-72. doi: 10.1152/ajpgi.00257.2015. Epub 2015 D

ec 23. PM

ID: 26702136. PM

CID

: PMC

4754741. 7. Puri P, Xu J, Vihervaara T, Katainen R

, Ekroos K, Daita K, M

in HK, Joyce A, M

irshahi F, Tsukam

oto H

, Sanyal

AJ. Alcohol

produces distinct

hepatic lipidom

e and

eicosanoid signature in lean and obese. J Lipid R

es. 2016 Jun;57(6):1017-28. doi: 10.1194/jlr.M066175.

Epub 2016 Mar 28. PM

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CID

: PMC

4878186. 8. Kw

eon SM

, Chi F, H

igashiyama R

, Lai K, Tsukamoto H

. Wnt Pathw

ay Stabilizes MeC

P2 Protein to R

epress PPAR-γ in Activation of H

epatic Stellate Cells. PLoS O

ne. 2016 May

23;11(5):e0156111. doi: 10.1371/journal.pone.0156111. eCollection 2016. PM

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PMC

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4877088. 9. C

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i YJ, Muñoz N

M, Kundra S, H

erlong HF, Jeong YS, G

oltsov A, O

hshiro K, Mistry N

A, Zhang J, Su X, Choufani S, M

itra A, Li S, Mishra B, W

hite J, Rashid

A, Wang AY, Javle M

, Davila M

, Michaely P, W

eksberg R, H

ofstetter WL, Finegold M

J, Shay JW

, M

achida K,

Tsukamoto

H,

Mishra

L. TG

F-β/β2-spectrin/CTC

F-regulated tum

or suppression in hum

an stem cell disorder Beckw

ith-Wiedem

ann syndrome. J C

lin Invest. 2016 Feb;126(2):527-42. doi: 10.1172/JC

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: 26934883. PM

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11. Lua I, Li Y, Zagory JA, Wang KS, French SW

, Sévigny J, Asahina K. Characterization of

hepatic stellate cells, portal fibroblasts, and mesothelial cells in norm

al and fibrotic livers. J H

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18. Wang L, Llorente C

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19. Ji C. Advances and N

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20. Brandl K, Schnabl B. Is intestinal inflamm

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27. Xu S, Chheda C

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R,

Mascariñas E, D

eCant B, Tsukam

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29. Vaitheesvaran B, Xu J, Yee J, Q-Y L, G

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. IL-8 signaling is up-regulated in alcoholic hepatitis and D

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thaya Kumar D

. B., Chen C

.L., Liu J.C., Feldm

an D., Sher L., French S., D

iNorcia

J., French S.W., N

aini B.V., Junrungsee S., Agopian V.G., Zarrinpar A., M

achida K. TLR4

Signaling via NAN

OG

Cooperates W

ith STAT3 to Activate Twist1 and Prom

ote Formation of

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-like Cells in Livers of M

ice. Gastroenterology. 2015 N

ov 12. pii: S0016-5085(15)01618-2. PM

ID: 26582088.

41. Siddique HR

, Feldman D

E, Chen C

L, Punj V, Tokumitsu H

, M

achida K. NU

MB

phosphorylation destabilizes p53 and promotes self-renew

al of tumor-initiating cells by

NAN

OG

-dependent mechanism

in liver cancer. Hepatology. 2015 N

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CID

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es. 2015 Nov 11. PM

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ole of Gut M

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Mem

ber G

rant Num

ber Title / Project Period / Annual D

C

Asahina, Kinji

1R21AA024840-01

DISSECTION

OF G

LISSON

'S CAPSULE IN

ALCO

HOL IN

DUCED LIVER IN

JURY. [08/20/16-

7/31/18; $143,750] Pandol, Stephen

1R01AA024464-01A1

TARGETIN

G PRO

TEIN KIN

ASE D IN ALCO

HOLIC

PANCREATITIS [09/01/16-6/30/21; $225,000]

PI/PD

Grant N

umber

Title / Project Period / Annual DC

Asahina, Kinji

1R21AA024840-01

DISSECTION

OF G

LISSON

'S CAPSULE IN

ALCO

HOL IN

DUCED LIVER IN

JURY. [08/20/16-

7/31/18; $143,750] Pandol, Stephen

1R01AA024464-01A1

TARGETIN

G PRO

TEIN KIN

ASE D IN ALCO

HOLIC

PANCREATITIS [09/01/16-6/30/21; $225,000]

1. Uthaya K

umar D

. B., C

hen C.L., Liu J.C

., Feldman D

., Sher L.S

., French S., D

iNorcia J.,

French S.W

., Naini B

.V., Junrungsee S

., Agopian V

.G., Zarrinpar A

., Machida K

. TLR4

Signaling via N

AN

OG

Cooperates W

ith STA

T3 to Activate Tw

ist1 and Prom

ote Formation of

Tumor-initiating

Stem

-like C

ells in

Livers of

Mice.

2016 M

ar;150(3):70710.1053/j.gastro.2015.11.002. E

pub 2015 Nov 12. P

MID

: 26582088. PM

CID

: PM

C4766021.

2. M

andrekar P

, B

ataller R

, Tsukam

oto H

, G

ao B

. A

lcoholic hepatitis:

Translational approaches to develop targeted therapies. H

epatology. 2016 Mar 3. doi: 10.1002/hep.28530.

[Epub ahead of print] P

MID

: 26940353. PM

CID

: PM

C5010788.

3. Mukherjee R

, Mareninova O

A, O

dinokova IV, H

uang W, M

urphy J, Chvanov M

, Javed MA

, W

en L, Booth D

M, C

ane MC

, Aw

ais M, G

avillet B, P

russ RM

, Schaller S

, Molkenti

Tepikin AV

, Petersen O

H, P

andol SJ, G


N, G

ukovskaya AS

, Sutton R

; N

IHR

P

ancreas B

iomedical

Research

Unit.M

echanism

of m

itochondrial perm

eability transition pore induction and dam

age in the pancreas: inhibition prevents acute pancreby protecting production of A

TP. G

ut. 2016 Aug;65(8):1333-46. doi: 10.1136/gutjnl

308553. Epub 2015 Jun 12. P

MID

: 26071131. PM

CID

: PM

C4920725.

4. Avila D

V, B

arker DF, Zhang J, M

cClain C

J, Barve S

, Gobejishvili L. D

ysregulation of hepatic cA

MP

levels via altered Pde4b expression plays a critical role in alcohol

steatosis. J Pathol. 2016 Jun 11. doi: 10.1002/path.4760. [E

pub ahead of print] PM

ID:

27287961. PM

CID

: PM

C4993672.

5. Chen C

L, Uthaya K

umar D

B, P

unj V, X

u J, Sher L, Tahara S

M, H

eN

AN

OG

Metabolically R

eprograms Tum

or-Initiating Stem

-like Cells through Tum

origenic C

hanges in Oxidative P

hosphorylation and Fatty Acid M

etabolism. C

ell Metab. 2016 Jan

12;23(1):206-19. doi: 10.1016/j.cmet.2015.12.004. E

pub 2015 Dec 24. P

MP

MC

ID: P

MC

4715587. 6. Li Y

, Lua I, French SW, A

sahina K. R

ole of TGF-β signaling in differentiation of m

esothelial cells to vitam

in A-poor hepatic stellate cells in liver fibrosis. A

m J P

hysiol Gastrointest Liver

Physiol. 2016 Feb 15;310(4):G

262-72. doi: 10.1152/ajpgi.00257.2015. Epub 2015 D

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2) Jun Xu - From Postdoctoral Fellow to Asst. Project Scientist.B) Grant Applications, and Funded Non-Federal Grants 1) Jun Xu - NIH R01 grant application submitted. 2) Takeshi Saito - AMBRF grant application submitted. 3) Douglas Feldman - NIH R21 and R01 grant applications submitted. 4) Keane Lai - Wright Foundation Pilot Award funded, and Stop Cancer Seed grant received. 5) Akiko Eguchi - Kakenhi grant funded. 6) Ramachandran Murali - CTSI/CTRC pilot project funded. [CONTINUED ON NEXT PAGE]

23. Wang P, Koyama Y, Liu X, Xu J, Ma HY, Liang S, Kim IH, Brenner DA, Kisseleva T. Promising Therapy Candidates for Liver Fibrosis. Front Physiol. 2016 Feb 16;7:47. PMCID: PMC4754444. 24. Liang S, Kisseleva T, Brenner DA. The Role of NADPH Oxidases (NOXs) in Liver Fibrosis and the Activation of Myofibroblasts. Front Physiol. 2016 Feb 2;7:17. PMCID: PMC4735448. 25. Liu H, French SW. Mallory Denk Body Formation in Alcoholic Hepatitis: The Pivotal Role of Interleukin-8 Signaling. Clin Microbiol. 2016 Feb;5(1). pii: 235. PMCID: PMC4807866. 26. Prieto-Domínguez N, Ordóñez R, Fernández A, Méndez-Blanco C, Baulies A, Garcia-Ruiz C, Fernández-Checa JC, Mauriz JL, González-Gallego J. Melatonin-induced increase in sensitivity of human hepatocellular carcinoma cells to sorafenib is associated with reactive oxygen species production and mitophagy. J Pineal Res. 2016 Oct;61(3):396-407. PMCID: PMC5018464. 27. Ribas V, García-Ruiz C, Fernández-Checa JC. Mitochondria, cholesterol and cancer cell metabolism. Clin Transl Med. 2016 Dec;5(1):22. PMCID: PMC4960093. 28. Stefanovic M, Tutusaus A, Martinez-Nieto GA, Bárcena C, de Gregorio E, Moutinho C, Barbero-Camps E, Villanueva A, Colell A, Marí M, García-Ruiz C, Fernandez-Checa JC, Morales A. Targeting glucosylceramide synthase upregulation reverts sorafenib resistance in experimental hepatocellular carcinoma. Oncotarget. 2016 Feb 16;7(7):8253-67. PMCID: PMC4884990. 29. Eguchi A, Lazaro, R, Wang J, Kim J, Povero D, Willliams B, Ho S, Stärkel P, Schnabl B, Ohno-Machado L, Tsukamoto H, Feldstein AE . Extracellular vesicles released by hepatocytes from gastric infusion model of ALD contain a miRNA barcode that can be detected in blood. Hepatology. 2016 Sep 17. PMID: 27639178. 30. Valente, T., Sidhu, A., Lee, J., Baezconde-Garbanati, L., Pandol, S., Saab, S., Mendler, M., Tsukamoto, H. Lagged versus Difference score regression: An example from a community based educational seminar evaluation. Pedagogy in Health Promotion. (In Press). ** 31. Wang L, Fouts DE, Stärkel P, Hartmann P, Chen P, Llorente C, DePew J, Moncera K, Ho SB, Brenner DA, Hooper LV, Schnabl B. Intestinal REG3 Lectins Protect Against Alcoholic Steatohepatitis by Reducing Mucosa-associated Microbiota and Preventing Bacterial Translocation. Cell Host Microbe. 2016 Feb 10;19(2):227-39. PMCID: PMC4786170. 32. French SW. Chronic alcohol binging injures the liver and other organs by reducing NAD⁺ levels required for sirtuin's deacetylase activity. Exp Mol Pathol. 2016 Apr;100(2):303-6. PMID: 26896648. 33. Bluemel S, Williams B, Knight R, Schnabl B. Precision Medicine in Alcoholic and Non-Alcoholic Fatty Liver Disease via Modulating the Gut Microbiota. Am J Physiol Gastrointest Liver Physiol. 2016 Sep 29:ajpgi.00245.2016. PMID: 27686615. 34. Ho SB, Matheny M, Schnabl B. Changes in hospital admissions and mortality for complications of cirrhosis: implications for clinicians and health systems. Gut Liver. 2016 Jan;10(1):8-9. PMCID: PMC4694728. 35. Nakamoto N, Schnabl B. Does the intestinal microbiota explain differences in the epidemiology of liver disease between East and West? Inflamm Intest Dis. 2016 Apr;1(1):3-8. PMCID: PMC4883108. 36. Schnabl B. Liver Capsule: Mechanisms of Alcoholic Hepatitis. Hepatology. 2016 Jul;64(1):276. PMID: 26867027. 37. Fuchs M, Schnabl B. Editors' Introduction to the NAFLD and NASH Special Issue. Dig Dis Sci. 2016 May;61(5):1211-3. PMID: 27068170. 38. Arroyo V, Moreau R, Kamath PS, Jalan R, Gines P, Nevens F, Fernandez J, To U, Garcia-Tsao G, Schnabl B. Acute-on-chronic liver failure in cirrhosis. Nat Rev Dis Primers. 2016 Jun 9;2:16041. PMID: 27277335. 39. Chen P, Miyamoto Y, Mazagova M, Lee K, Eckmann L, Schnabl B. Microbiota and Alcoholic Liver Disease. Alcohol Clin Exp Res. 2016 Aug;40(8):1791-2. PMID: 27364225. 40. Llorente C, Schnabl B. Fast-track clearance of bacteria from the liver. Cell Host Microbe. 2016 Jul 13;20(1):1-2. PMID: 27414492. 41. He L, Gubbins J, Peng Z, Medina V, Fei F, Asahina K, Wang J, Kahn M, Rountree CB, Stiles BL. Activation of hepatic stellate cell in Pten null liver injury model. Fibrogenesis Tissue Repair. 2016 Jun 14;9:8. PMCID: PMC4908727. 42. DeLeve LD, Wang X, Wang L. VEGF-sdf1 recruitment of CXCR7+ bone marrow progenitors of liver sinusoidal endothelial cells promotes rat liver regeneration. Am J Physiol Gastrointest Liver Physiol. 2016 May 1;310(9):G739-46. PMCID: PMC4867332. 43. Pham H, Birtolo C, Chheda C, Yang W, Rodriguez MD, Liu ST, Gugliotta G, Lewis MS, Cirulli V, Pandol SJ, Ptasznik A. Essential Role of Lyn in Fibrosis. Front Physiol. 2016 Aug 31;7:387. PMCID: PMC5006658. 44. Setiawan VW, Pandol SJ, Porcel J, Wei PC, Wilkens LR, Le Marchand L, Pike MC, Monroe KR. Dietary Factors Reduce Risk of Acute Pancreatitis in a Large Multiethnic Cohort. Clin Gastroenterol Hepatol. 2016 Sep 5. pii: S1542-3565(16)30619-X. PMID: 27609706. 45. Chen C.L., Huang, J., Wang, J., Zhou L., Kondo, Y., Schechter J., Su L., Lai M.M., Wakita, T., Cosset F.L., Jung. J., Machida K., Memory B cells are infected with lymphotropic hepatitis C virus through novel co-receptor B7.2, Nature Communications, Accepted, 2016. 46. Ma HY, Xu J, Liu X, Zhu Y, Gao B, Karin M, Tsukamoto H, Jeste DV, Grant I, Roberts AJ, Contet C, Geoffroy C, Zheng B, Brenner D, Kisseleva T. The role of IL-17 signaling in regulation of the liver-brain axis and intestinal permeability in Alcoholic Liver Disease. Curr Pathobiol Rep. 2016 Mar;4(1):27-35. PMCID: PMC4878828. 47. Chen S, Kang Y, Sun Y, Zhong Y, Li Y, Deng L, Tao J, Li Y, Tian Y, Zhao Y, Cheng J, Liu W, Feng GS, Lu Z. Deletion of Gab2 in mice protects against hepatic steatosis and steatohepatitis: a novel therapeutic target for fatty liver disease. J Mol Cell Biol. 2016 Jun 9. PMID: 27282405. 48. Nuño-Lámbarri N, Domínguez-Pérez M, Baulies-Domenech A, Monte MJ, Marin JJ, Rosales-Cruz P, Souza V, Miranda RU, Bucio L, Montalvo-Jave EE, Concepción Gutiérrez-Ruiz M, García-Ruiz C, Fernández-Checa JC, Gomez-Quiroz LE. Liver Cholesterol Overload Aggravates Obstructive Cholestasis by Inducing Oxidative Stress and Premature Death in Mice. Oxid Med Cell Longev. 2016;2016:9895176. PMCID: PMC5011220. 49. Gao B, Tsukamoto H. Inflammation in Alcoholic and Nonalcoholic Fatty Liver Disease: Friend or Foe? Gastroenterology. 2016 Jun;150(8):1704-9. PMCID: PMC4887345. 50. Kim IH, Xu J, Liu X, Koyama Y, Ma HY, Diggle K, You YH, Schilling JM, Jeste D, Sharma K, Brenner DA, Kisseleva T. Aging increases the susceptibility of hepatic inflammation, liver fibrosis and aging in response to high-fat diet in mice. Age (Dordr). 2016 Aug 30. PMCID: PMC5061686. 51. Harrall KK, Kechris KJ, Tabakoff B, Hoffman PL, Hines LM, Tsukamoto H, Pravenec M, Printz M, Saba LM. Uncovering the liver's role in immunity through RNA co-expression networks. Mamm Genome. 2016 Oct;27(9-10):469-84. PMCID: PMC5002042.

** Director’s selected highlights

1. Uthaya Kumar D. B., Chen C.L., Liu J.C., Feldman D., Sher L.S., French S., DiNorcia J., French S.W., Naini B.V., Junrungsee S., Agopian V.G., Zarrinpar A., Machida K. TLR4 Signaling via NANOG Cooperates With STAT3 to Activate Twist1 and Promote Formation of Tumor-initiating Stem-like Cells in Livers of Mice. Gastroenterology. 2016 Mar;150(3):707-19. PMCID: PMC4766021. 2. Mandrekar P, Bataller R, Tsukamoto H, Gao B. Alcoholic hepatitis: Translational approaches to develop targeted therapies. Hepatology. 2016 Mar 3. PMCID: PMC5010788. 3. Mukherjee R, Mareninova OA, Odinokova IV, Huang W, Murphy J, Chvanov M, Javed MA, Wen L, Booth DM, Cane MC, Awais M, Gavillet B, Pruss RM, Schaller S, Molkentin JD, Tepikin AV, Petersen OH, Pandol SJ, Gukovsky I, Criddle DN, Gukovskaya AS, Sutton R; NIHR Pancreas Biomedical Research Unit.Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: inhibition prevents acute pancreatitis by protecting production of ATP. Gut. 2016 Aug;65(8):1333-46. PMCID: PMC4920725. 4. Avila DV, Barker DF, Zhang J, McClain CJ, Barve S, Gobejishvili L. Dysregulation of hepatic cAMP levels via altered Pde4b expression plays a critical role in alcohol-induced steatosis. J Pathol. 2016 Jun 11. PMCID: PMC4993672. ** 5. Chen CL, Uthaya Kumar DB, Punj V, Xu J, Sher L, Tahara SM, Hess S, Machida K. NANOG Metabolically Reprograms Tumor-Initiating Stem-like Cells through Tumorigenic Changes in Oxidative Phosphorylation and Fatty Acid Metabolism. Cell Metab. 2016 Jan 12;23(1):206-19. PMCID: PMC4715587. 6. Li Y, Lua I, French SW, Asahina K. Role of TGF-β signaling in differentiation of mesothelial cells to vitamin A-poor hepatic stellate cells in liver fibrosis. Am J Physiol Gastrointest Liver Physiol. 2016 Feb 15;310(4):G262-72. PMCID: PMC4754741. 7. Puri P, Xu J, Vihervaara T, Katainen R, Ekroos K, Daita K, Min HK, Joyce A, Mirshahi F, Tsukamoto H, Sanyal AJ. Alcohol produces distinct hepatic lipidome and eicosanoid signature in lean and obese. J Lipid Res. 2016 Jun;57(6):1017-28. PMCID: PMC4878186. 8. Kweon SM, Chi F, Higashiyama R, Lai K, Tsukamoto H. Wnt Pathway Stabilizes MeCP2 Protein to Repress PPAR-γ in Activation of Hepatic Stellate Cells. PLoS One. 2016 May 23;11(5):e0156111. PMCID: PMC4877088. 9. Chen J, Yao ZX, Chen JS, Gi YJ, Muñoz NM, Kundra S, Herlong HF, Jeong YS, Goltsov A, Ohshiro K, Mistry NA, Zhang J, Su X, Choufani S, Mitra A, Li S, Mishra B, White J, Rashid A, Wang AY, Javle M, Davila M, Michaely P, Weksberg R, Hofstetter WL, Finegold MJ, Shay JW, Machida K, Tsukamoto H, Mishra L. TGF-β/β2-spectrin/CTCF-regulated tumor suppression in human stem cell disorder Beckwith-Wiedemann syndrome. J Clin Invest. 2016 Feb;126(2):527-42. PMCID: PMC4731168. 10. Lua I, Asahina K. The Role of Mesothelial Cells in Liver Development, Injury, and Regeneration. Gut Liver. 2016 Mar;10(2):166-76. PMCID: PMC4780447. ** 11. Lua I, Li Y, Zagory JA, Wang KS, French SW, Sévigny J, Asahina K. Characterization of hepatic stellate cells, portal fibroblasts, and mesothelial cells in normal and fibrotic livers. J Hepatol. 2016 May;64(5):1137-46. PMCID: PMC4834254. ** 12. Cho NE, Bang BR, Gurung P, Li M, Clemens DL, Underhill TM, James LP, Chase JR, Saito T. Retinoid regulation of antiviral innate immunity in hepatocytes. Hepatology. 2016 Jun;63(6):1783-95. PMCID: PMC4874888. 13. Habtezion A, Edderkaoui M, Pandol SJ. Macrophages and pancreatic ductal adenocarcinoma. Cancer Lett. 2015 Dec 18. pii: S0304-3835(15)00746-6. PMCID: PMC4912945. 14. Edderkaoui M, Xu S, Chheda C, Morvaridi S, Hu RW, Grippo PJ, Mascariñas E, Principe DR, Knudsen B, Xue J, Habtezion A, Uyeminami D, Pinkerton KE, Pandol SJ. HDAC3 mediates smoking-induced pancreatic cancer. Oncotarget. 2016 Feb 16;7(7):7747-60. PMCID: PMC4884951. 15. Gukovskaya AS, Pandol SJ, Gukovsky I. New insights into the pathways initiating and driving pancreatitis.Curr Opin Gastroenterol. 2016 Jul 13. PMID: 27428704. ** 16. Su HY, Waldron RT, Gong R, Ramanujan VK, Pandol SJ, Lugea A. The Unfolded Protein Response Plays a Predominant Homeostatic Role in Response to Mitochondrial Stress in Pancreatic Stellate Cells. PLoS One. 2016 Feb 5;11(2):e0148999. PMCID: PMC4743835. 17. Setiawan VW, Pandol SJ, Porcel J, Wilkens LR, Le Marchand L, Pike MC, Monroe KR. Prospective Study of Alcohol Drinking, Smoking, and Pancreatitis: The Multiethnic Cohort. Pancreas. 2016 Jul;45(6):819-25. PMCID: PMC4905778. 18. Quinn BA, Wang S, Barile E, Das SK, Emdad L, Sarkar D, De SK, Morvaridi SK, Stebbins JL, Pandol SJ, Fisher PB, Pellecchia M. Therapy of pancreatic cancer via an EphA2 receptor-targeted delivery of gemcitabine. Oncotarget. 2016 Mar 29;7(13):17103-10. PMCID: PMC4941374. 19. Birtolo C, Go VL, Ptasznik A, Eibl G, Pandol SJ. Phosphatidylinositol 3-Kinase: A Link Between Inflammation and Pancreatic Cancer. Pancreas. 2016 Jan;45(1):21-31. PMCID: PMC4859755. 20. Subramanian VS, Srinivasan P, Said HM. Uptake of ascorbic acid by pancreatic acinar cells is negatively impacted by chronic alcohol exposure. Am J Physiol Cell Physiol. 2016 Jul 1;311(1):C129-35. PMCID: PMC4967129. 21. Yuan J, Pandol SJ. PKD signaling and pancreatitis. J Gastroenterol. 2016 Jul;51(7):651-9. PMCID: PMC4921304. 22. Koyama Y, Xu J, Liu X, Brenner DA. New Developments on the Treatment of Liver Fibrosis. Dig Dis. 2016;34(5):589-96. PMCID: PMC4961096.

PI/P

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PI/PD Grant Number Title / Project Period / Annual DC

Asahina, Kinji 1R21AA024840-01

DISSECTION OF GLISSON'S CAPSULE IN ALCOHOL INDUCED LIVER INJURY. [8/20/16-7/31/18; $143,750]

Pandol, Stephen

1R01AA024464-01A1

TARGETING PROTEIN KINASE D IN ALCOHOLIC PANCREATITIS [9/1/16-6/30/21; $225,000]

Schnabl, Bernd

5R01AA020703-06A

MICROBIOME AND INTESTINAL INNATE IMMUNE RESPONSE IN ALCOHOLIC LIVER DISEASE [9/25/11-6/30/21; $225,000]

Tsukamoto, Hidekazu

2R24AA012885-16

INTEGRATIVE LIVER CELL CORE [6/1/01-5/31/21; $292,743]

Tsukamoto, Hidekazu

5R13AA020691-06

INTERNATIONAL SYMPOSIUM ON ALPD AND CIRRHOSIS [8/5/11-4/30/21; $50,000]

RECENT GRANTS AND PUBLICATIONS (2016)BY CENTER MEMBERS


www.usc.edu/alpd


One speci�c and notable outcome of the outreach e�orts associated with the 7th International Symposium (2012) was the establishment of the ALD Research Center in Beijing’s 302 Hospital, facilitated in part by Bin Gao, M.D., Ph.D. (Advisory Committee Chair). One year before, outreach e�orts associated with the 6th Symposium (2011) contributed in part to passing and enactment of the �rst Alcohol Health Problems Countermeasures Basic Law in 2014 in Japan. [CONTINUED ON NEXT PAGE]


CONTACTSHidekazu Tsukamoto Director [email protected] 323-442-5107

Sean Kohlmeier Program Administrator [email protected] 323-442-3109

Asma Deras Budget Analyst [email protected] 323-442-3121

Fax: 323-442-3126 www.usc.edu/alpd

Editor: Sean Kohlmeier

The Southern California Research Center for ALPD and Cirrhosis recently submitted a renewal for the NIAAA R13 grant that provides funding for its International Symposium program. Dating back to 2006, the Center has long considered this program to be the most e�ective means to stimulate new and integrated scienti�c approaches in research and global collaboration related to ALPD among various countries. During the last funding cycle, the R13 Grant supported the Center’s co-sponsorship of symposia in Japan, China, India, Hungary, and Brazil. These meetings were represented by 10-15 nations, attracting the attendance of 155-475 per event.

Of note, the International Symposia are sponsored by key academic organizations of the hosting nations to achieve a maximal outcome of the outreachobjective in those nations. The recent meetings have catalyzed active international collaborations among investigators with complementary expertise and resources, resulted in 11 peer-review publications and acquisition of 3 grants, and led to major advancements of science in the �eld of ALPD and cirrhosis.

- Beijing, China | September 6-7, 2012- Theme: Alcohol, Viral Hepatitis, and Pancreatitis: New Challenges

- New Delhi, India | November 16-17, 2013- Theme: Alcohol, Infection, and Cancer

- Sao Paulo, Brazil | September 30-October 1, 2015- Theme: Alcohol, Virus, and Steatosis Evolving to Cancer

- Szeged, Hungary | November 22-23, 2014- Theme: Cellular Metabolism in Alcohol-Induced Panc & Liver Diseases

THE INTERNATIONAL SYMPOSIUM ON ALPD AND CIRRHOSIS: A LOOK BACK AT THE PAST 5 YEARS…

6th International Symposium on ALPD and Cirrhosis





- Fukuoka, Japan | October 20-21, 2011- Theme: From Stem Cells to Global Health



R24 AA012885 and R13 AA020691.

INSIDE THIS ISSUE

1 International Symposium in Review

2 Spotlight on Takeshi Saito

3 The Integrative Liver Cell Core

3 Clinical Center Feature

4 Program Project Grant Feature

4 Recent Grants Acquiredby Center Members

5 Lee Summer Research

Fellowship Program

5

2015 Publications by

Center Members

(L) Raj Lakshman, Xiao-Ming Yin, Bin Gao, Peter HegyiEdna Strauss, Arun Sanyal in Sao Paulo, Brazil 2015

NEW ANIMAL CORE MODEL: PATIENT-DERIVED XENOGRAFT (PDX)As captured in the Table on , the Center o�ers a variety of animal models via its Animal Core. New models are constantly in development. One such new model, to be made available in late 2016/early 2017, is the Patient-Derived Xenograft (PDX) model. To promote translational signi�cance of alcohol-promoted Hepatocellular Carcinoma (HCC) and Pancreatic Ductal Adenocarcinoma (PDAC) studies that are being pursued by Center investigators, the Center’s Animal Core has established a consortium with USC’s Departments of Surgery and Pathology. The Animal Core has arranged to receive freshly excised human liver or pancreatic cancer from the Surgery Department, which will be used to perform Patient-Derived Xenograft (PDX) transplantation into immunode�cient NSG mice. The growing human cells will then be collected from the animals, after which the cells will be re-implanted into separate animals for continued growth. And so on. In other words, the Center's Animal Core will be establishing a "living repository" of human liver/pancreas cancer using this PDX model. By expanding and maintaining growing human tissue in this manner, both Center investigators and non-center investigators alike will be able to perform innovative and important biomedical research.

The Center co-organized the 11th annual International Symposium on Alcoholic Liver and Pancreatic Diseases and Cirrhosis from September 2-3, 2016 as a satellite symposium for the ISBRA/ESBRA World Congress in Berlin, Germany. It’s theme was “EmergingTherapuetic Targets.” The organizing committee included, CenterDirector, Hidekazu Tsukamoto, who served along with Helmut Karl Seitz from the University of Heidelberg, Samir Zakari from DISCUS,

www.usc.edu/alpd 4

11th INTERNATIONAL SYMPOSIUM ON ALPD AND CIRRHOSIS (2016): BERLIN, GERMANY


RENEWAL OF THE INTEGRATIVE LIVER CELL COREThe Center has successfully renewed its Non-Parenchymal Liver CellCore grant under the new name, “Integrative Liver Cell Core” (ILCC). The grant (R24AA012885) is in its15th year. Through 2020, this $2.1M award will continue to support the Core’s leading-edge activities as a national resource for isolation and lineage tracing of di�erent liver cell types in animal models of alcoholic liver disease (ALD) and alcohol-promoted liver cancer produced by the Center’s Animal Core. During the past funding cycle, the ILCC served 31 investigators from 10 institutions by performing 2,204 isolation preparations, supporting 34 publications and acquisition and continuation of 18 NIH grants by a total of 20 investigators including 7 non-center investigators across the nation. The ILCC also supported the career development of 9 early-career investigators through their cell type speci�c research and grant acquisitions. The ILCC aims to further advance its unique services to promote genetic, epigenetic, metabolic, and molecular research on altered cell fate regulation of di�erent liver cell types which manifest as fundamental mechanisms underlying in�ammation, �brosis, and tumorigenesis in ALPD.

www.usc.edu/alpd 3

Morphology CoreThe Center’s Morphology Core headed by Dr. Samuel French, has served many center members m 2013-2016, resultingin in 35+publications on research supported by the Core.


7) Karsten Zengler - UCSD/FISP grant funded. 8) Shabnam Shalapour - NIH R01 grant application submitted (as Co-Investigator). 9) Kinji Asahina - USC Dean’s Pilot Funding Program

In SummaryThe outcome data strongly indicates that the Center continues to acheive its core goals: 1) creating an environment conducive for leading-edge research on the center’s theme: elucidation of the priming and sensitizing mechanisms for ALPD and cirrhosis; 2) providing unique models, innovative genetic approaches and expertise to outside investigators including those at other NIAAA Alcohol Research Centers; 3) providing comprehensive education and training to foster future generations of scientists in ALPD and cirrhosis; 4) organizing outreach e�orts to disseminate the center’s new �ndings to lay public, health care workers and scientists in our home and global communities.

TABLE OF ANIMAL CORE MODELS

Alcohol ad lib Feeding Model

Obesity and NASH Model

Liver Cancer Promotion Model

PDAC Promotion Model

Non-Alcohol Liver Fibrosis Model

Liver Regeneration Model

TIC Transplantation Model

Gavage

1. iG-Std 2. Hybrid HCFD+Alc iG

1. Ad lib-Std 2. Ad lib-Std+Cearulein3. Ad lib HCFD+Alc+Binge

1. iG-OF2. Ad lib (HCFD pellet)

1. Ad lib-Std-NNK+Cerulein

1. CCL42. BDL

1. Partial Hepatecotomy

1. TICs Orthotopic Transplantation2. TICs Subcutaneous

1. Medication

3. Hybrid HCFD+Alc iG+Binge

1. DEN+chow 2. DEN+Ad lib(pellets)3. DEN+PB 4. DEN+Ad Lib HCFD+Alc

Alcohol iG or Hybrid Feeding Model

Center Mem

ber G

rant Num

ber Title

Project Period Annual DC


DISSECTION

OF GLISSO

N'S CAPSU

LE IN ALCO

HOL IN

DUCED

LIVER INJU

RY. 08/20/16-7/31/18

$143,750

Eguchi, Akiko R21AA023574-02

ENCAPSU

LATED RNAS IN

EXTRACELLULAR VESICLES CO

NTRIBU

TE ALD PROGRESSIO

N

9/5/15-8/31/17 $118,750

Feng, Gen-Sheng

1R01CA188506-02 DISSECTIO

N O

F PTEN-REGU

LATED SIGNALS IN

HEPATO

PATHOGEN

ESIS 7/1/15-6/30/20

$228,750 Pandol, Stephen

1R01AA024464-01A1 TARGETIN

G PROTEIN

KINASE D IN

ALCOHO

LIC PANCREATITIS

09/01/16-6/30/21 $225,000

Pandol, Stephen 1U

01DK108314-02 PATHO

PHYSIOLO

GY, EPIDEMIO

LOGY, AN

D PREVENTIO

N O

F PAN

CREATOGEN

IC DIABETES 9/28/15-8/31/20

$268,926 Saito, Takeshi

1R21AA022751-02 RETIN

OID REGU

LATION

OF HEPATIC IN

NATE IM

MU

NITY

8/20/14-7/31/17 $115,187

Saito, Takeshi 1R01DK101773-02

INN

ATE DEFENSE PRO

GRAM AGAIN

ST HCV 5/1/15-3/31/20

$225,000

Zhong, Shuping 1R21AA023247-02

FUN

CTION

OF RU

NX2 IN

ALCOHO

L-ASSOCIATED BREAST

CANCER

1/25/14-8/31/17 $145,400

and Bin Gao from NIH/NIAAA. Speakers for the event represented a wide range of countries, including Chile, Japan, Germany, Sweden, Italy,and the United States. The Center competitively selected nine travel awardees ($1,500 each) drawn from a pool of young investigator applicants. This was made possible by Dr. Tsukamoto’s R13 (2R13 AA020691) grant. All nine of the travel awardees presented posters while in Berlin, and �ve of them additionally participated in the symposium’s Program by giving oral presentations.

The 12th and 13th International Symposia are scheduled to tak eplace in Tokyo and Kyoto, Japan, jointly sponsored by Japanese Society ofGastroentrology and ISBRA2018 on April 19, and September 9, 2018, respectively.

In terms of attendance for the 2016 ISBRA/ESBRA, there were 560 total participants, from 43 countries. 148 of all participants were from the United States. 210 of the total number of participants were female (50 from the U.S.). 209 of the participants were ISBRA/ESBRA members.

2016 LEE SUMMER RESEARCH FELLOWSHIP PROGRAM CONGRATULATIONS to the students selected for the Lee Summer Research

Fellowship Program, supported by the Center!

Student

Project M

entor

Ingmar B

astian IgA

producing plasmocytes in A

SH

, N

AS

H, and H

CC

M

ichael Karin

Dina

Hauptschein

Mechanism

s of pancreatic cancer chem

oresistance S

tephen Pandol

Brook

Mehregany

IL-17 signaling regulates alcohol-induced changes in liver-brain axis

Tatiana Kisseleva

Madhuri R

ao E

ffects of mitochondrial m

orphology on alcohol m

etabolism

Derick H

an

Student Project Mentor

Ingmar Bastian

IgA producing plasmocytes in ASH, NASH, and HCC

Michael Karin

Dina Hauptschein

Mechanisms of pancreatic cancer chemoresistance

Stephen Pandol

Brook Mehregany


Tatiana Kisseleva

Madhuri Rao

Effects of mitochondrial morphology on alcohol metabolism

Derick Han

Elton Zhou

Human amniotic epithelial cell-derived exosomal miR483-5p in hepatic stellate cell modulation

Toshio Miki

Shane Zhou MKK4/7 in JNK activation and hepatotoxicity Neil Kaplowitz

Yunheng Zhu

The inactivation of human HSCs and its implications for alcoholic liver disease therapy

David Brenner

Basic services Cell Bank

DirectorHide Tsukamoto

[email protected]

Research ScientistRaymond Wu

[email protected]

Financial AnalystAsma Deras

[email protected]

Lab SpecialistStephanie Pan

[email protected] Directors

Kinji [email protected]

Jun [email protected]

Our expert team

Special services. .

EducationAs part of its commitment to educating new investigators, andfacilitating collaboration among scientists in the �elds of ALPD, Cirrhosis and closely related biologies, the Center administers two educational programs at USC: The Lee Summer Research Fellowship and a graduate course, Pathology 575. The former program provides an opportunity for young students to work throughout the summer with Center Members who agree to serve as their mentors. Each student presents his/her work during the Center’s annual Progress Report meeting. Between 2013-2016, 31 students completed the Lee Summer Reserach Fellowship, earning a certi�cate and (where applicable) a cash award of $800. Forthe USC PATH 575 graduate course (entitled, the “Cellular Homeostasis Lecture Series”), which is entirely sponsored by the center,Center members are involved in hosting, coordinating, and lecturing on topics related to the Center’s themes. Between 2013-2016, 41 graduate students completed the course.


www.usc.edu/alpd


One speci�c and notable outcome of the outreach e�orts associated with the 7th International Symposium (2012) was the establishment of the ALD Research Center in Beijing’s 302 Hospital, facilitated in part by Bin Gao, M.D., Ph.D. (Advisory Committee Chair). One year before, outreach e�orts associated with the 6th Symposium (2011) contributed in part to passing and enactment of the �rst Alcohol Health Problems Countermeasures Basic Law in 2014 in Japan. [CONTINUED ON NEXT PAGE]


CONTACTSHidekazu Tsukamoto Director [email protected] 323-442-5107

Sean Kohlmeier Program Administrator [email protected] 323-442-3109

Asma Deras Budget Analyst [email protected] 323-442-3121

Fax: 323-442-3126 www.usc.edu/alpd

Editor: Sean Kohlmeier

The Southern California Research Center for ALPD and Cirrhosis recently submitted a renewal for the NIAAA R13 grant that provides funding for its International Symposium program. Dating back to 2006, the Center has long considered this program to be the most e�ective means to stimulate new and integrated scienti�c approaches in research and global collaboration related to ALPD among various countries. During the last funding cycle, the R13 Grant supported the Center’s co-sponsorship of symposia in Japan, China, India, Hungary, and Brazil. These meetings were represented by 10-15 nations, attracting the attendance of 155-475 per event.

Of note, the International Symposia are sponsored by key academic organizations of the hosting nations to achieve a maximal outcome of the outreachobjective in those nations. The recent meetings have catalyzed active international collaborations among investigators with complementary expertise and resources, resulted in 11 peer-review publications and acquisition of 3 grants, and led to major advancements of science in the �eld of ALPD and cirrhosis.

- Beijing, China | September 6-7, 2012- Theme: Alcohol, Viral Hepatitis, and Pancreatitis: New Challenges

- New Delhi, India | November 16-17, 2013- Theme: Alcohol, Infection, and Cancer

- Sao Paulo, Brazil | September 30-October 1, 2015- Theme: Alcohol, Virus, and Steatosis Evolving to Cancer

- Szeged, Hungary | November 22-23, 2014- Theme: Cellular Metabolism in Alcohol-Induced Panc & Liver Diseases

THE INTERNATIONAL SYMPOSIUM ON ALPD AND CIRRHOSIS: A LOOK BACK AT THE PAST 5 YEARS…






- Fukuoka, Japan | October 20-21, 2011- Theme: From Stem Cells to Global Health



R24 AA012885 and R13 AA020691.

INSIDE THIS ISSUE

1 International Symposium in Review

2 Spotlight on Takeshi Saito

3 The Integrative Liver Cell Core

3 Clinical Center Feature

4 Program Project Grant Feature

4 Recent Grants Acquiredby Center Members

5 Lee Summer Research

Fellowship Program

5

2015 Publications by

Center Members

(L) Raj Lakshman, Xiao-Ming Yin, Bin Gao, Peter HegyiEdna Strauss, Arun Sanyal in Sao Paulo, Brazil 2015

NEW ANIMAL CORE MODEL: PATIENT-DERIVED XENOGRAFT (PDX)As captured in the Table on Page 3, the Center o�ers a variety of animal models via its Animal Core. New models are constantly in development. One such new model, to be made available in late 2016/early 2017, is the Patient-Derived Xenograft (PDX) model. To promote translational signi�cance of alcohol-promoted Hepatocellular Carcinoma (HCC) and Pancreatic Ductal Adenocarcinoma (PDAC) studies that are being pursued by Center investigators, the Center’s Animal Core has established a consortium with USC’s Departments of Surgery and Pathology. The Animal Core has arranged to receive freshly excised human liver or pancreatic cancer from the Surgery Department, which will be used to perform Patient-Derived Xenograft (PDX) transplantation into immunode�cient NSG mice. The growing human cells will then be collected from the animals, after which the cells will be re-implanted into separate animals for continued growth. And so on. In other words, the Center's Animal Core will be establishing a "living repository" of human liver/pancreas cancer using this PDX model. By expanding and maintaining growing human tissue in this manner, both Center investigators and non-center investigators alike will be able to perform innovative and important biomedical research.

The Center co-organized the 11th annual International Symposium on Alcoholic Liver and Pancreatic Diseases and Cirrhosis from September 2-3, 2016 as a satellite symposium for the ISBRA/ESBRA World Congress in Berlin, Germany. It’s theme was “EmergingTherapuetic Targets.” The organizing committee included, CenterDirector, Hidekazu Tsukamoto, who served along with Helmut Karl Seitz from the University of Heidelberg, Samir Zakari from DISCUS,

www.usc.edu/alpd 4

11th INTERNATIONAL SYMPOSIUM ON ALPD AND CIRRHOSIS (2016): BERLIN, GERMANY


RENEWAL OF THE INTEGRATIVE LIVER CELL COREThe Center has successfully renewed its Non-Parenchymal Liver CellCore grant under the new name, “Integrative Liver Cell Core” (ILCC). The grant (R24AA012885) is in its15th year. Through 2020, this $2.1M award will continue to support the Core’s leading-edge activities as a national resource for isolation and lineage tracing of di�erent liver cell types in animal models of alcoholic liver disease (ALD) and alcohol-promoted liver cancer produced by the Center’s Animal Core. During the past funding cycle, the ILCC served 31 investigators from 10 institutions by performing 2,204 isolation preparations, supporting 34 publications and acquisition and continuation of 18 NIH grants by a total of 20 investigators including 7 non-center investigators across the nation. The ILCC also supported the career development of 9 early-career investigators through their cell type speci�c research and grant acquisitions. The ILCC aims to further advance its unique services to promote genetic, epigenetic, metabolic, and molecular research on altered cell fate regulation of di�erent liver cell types which manifest as fundamental mechanisms underlying in�ammation, �brosis, and tumorigenesis in ALPD.

www.usc.edu/alpd 3

Morphology CoreThe Center’s Morphology Core headed by Dr. Samuel French, has served many center members m 2013-2016, resultingin in 35+publications on research supported by the Core.


7) Karsten Zengler - UCSD/FISP grant funded. 8) Shabnam Shalapour - NIH R01 grant application submitted (as Co-Investigator). 9) Kinji Asahina - USC Dean’s Pilot Funding Program

In SummaryThe outcome data strongly indicates that the Center continues to acheive its core goals: 1) creating an environment conducive for leading-edge research on the center’s theme: elucidation of the priming and sensitizing mechanisms for ALPD and cirrhosis; 2) providing unique models, innovative genetic approaches and expertise to outside investigators including those at other NIAAA Alcohol Research Centers; 3) providing comprehensive education and training to foster future generations of scientists in ALPD and cirrhosis; 4) organizing outreach e�orts to disseminate the center’s new �ndings to lay public, health care workers and scientists in our home and global communities.

TABLE OF ANIMAL CORE MODELS

Alcohol ad lib Feeding Model

Obesity and NASH Model

Liver Cancer Promotion Model

PDAC Promotion Model

Non-Alcohol Liver Fibrosis Model

Liver Regeneration Model

TIC Transplantation Model

Gavage

1. iG-Std 2. Hybrid HCFD+Alc iG

1. Ad lib-Std 2. Ad lib-Std+Cearulein3. Ad lib HCFD+Alc+Binge

1. iG-OF2. Ad lib (HCFD pellet)

1. Ad lib-Std-NNK+Cerulein

1. CCL42. BDL

1. Partial Hepatecotomy

1. TICs Orthotopic Transplantation2. TICs Subcutaneous

1. Medication

3. Hybrid HCFD+Alc iG+Binge

1. DEN+chow 2. DEN+Ad lib(pellets)3. DEN+PB 4. DEN+Ad Lib HCFD+Alc

Alcohol iG or Hybrid Feeding Model

Center Mem

ber G

rant Num

ber Title

Project Period Annual DC


DISSECTION

OF GLISSO

N'S CAPSU

LE IN ALCO

HOL IN

DUCED

LIVER INJU

RY. 08/20/16-7/31/18

$143,750

Eguchi, Akiko R21AA023574-02

ENCAPSU

LATED RNAS IN

EXTRACELLULAR VESICLES CO

NTRIBU

TE ALD PROGRESSIO

N

9/5/15-8/31/17 $118,750

Feng, Gen-Sheng

1R01CA188506-02 DISSECTIO

N O

F PTEN-REGU

LATED SIGNALS IN

HEPATO

PATHOGEN

ESIS 7/1/15-6/30/20

$228,750 Pandol, Stephen

1R01AA024464-01A1 TARGETIN

G PROTEIN

KINASE D IN

ALCOHO

LIC PANCREATITIS

09/01/16-6/30/21 $225,000

Pandol, Stephen 1U

01DK108314-02 PATHO

PHYSIOLO

GY, EPIDEMIO

LOGY, AN

D PREVENTIO

N O

F PAN

CREATOGEN

IC DIABETES 9/28/15-8/31/20

$268,926 Saito, Takeshi

1R21AA022751-02 RETIN

OID REGU

LATION

OF HEPATIC IN

NATE IM

MU

NITY

8/20/14-7/31/17 $115,187

Saito, Takeshi 1R01DK101773-02

INN

ATE DEFENSE PRO

GRAM AGAIN

ST HCV 5/1/15-3/31/20

$225,000

Zhong, Shuping 1R21AA023247-02

FUN

CTION

OF RU

NX2 IN

ALCOHO

L-ASSOCIATED BREAST

CANCER

1/25/14-8/31/17 $145,400

and Bin Gao from NIH/NIAAA. Speakers for the event represented a wide range of countries, including Chile, Japan, Germany, Sweden, Italy,and the United States. The Center competitively selected nine travel awardees ($1,500 each) drawn from a pool of young investigator applicants. This was made possible by Dr. Tsukamoto’s R13 (2R13 AA020691) grant. All nine of the travel awardees presented posters while in Berlin, and �ve of them additionally participated in the symposium’s Program by giving oral presentations.

The 12th and 13th International Symposia are scheduled to tak eplace in Tokyo and Kyoto, Japan, jointly sponsored by Japanese Society ofGastroentrology and ISBRA2018 on April 19, and September 9, 2018, respectively.

In terms of attendance for the 2016 ISBRA/ESBRA, there were 560 total participants, from 43 countries. 148 of all participants were from the United States. 210 of the total number of participants were female (50 from the U.S.). 209 of the participants were ISBRA/ESBRA members.

2016 LEE SUMMER RESEARCH FELLOWSHIP PROGRAM CONGRATULATIONS to the students selected for the Lee Summer Research

Fellowship Program, supported by the Center!

Student

Project M

entor

Ingmar B

astian IgA

producing plasmocytes in A

SH

, N

AS

H, and H

CC

M

ichael Karin

Dina

Hauptschein

Mechanism

s of pancreatic cancer chem

oresistance S

tephen Pandol

Brook

Mehregany


Tatiana Kisseleva

Madhuri R

ao E

ffects of mitochondrial m

orphology on alcohol m

etabolism

Derick H

an

Student Project Mentor

Ingmar Bastian

IgA producing plasmocytes in ASH, NASH, and HCC

Michael Karin

Dina Hauptschein

Mechanisms of pancreatic cancer chemoresistance

Stephen Pandol

Brook Mehregany


Tatiana Kisseleva

Madhuri Rao

Effects of mitochondrial morphology on alcohol metabolism

Derick Han

Elton Zhou

Human amniotic epithelial cell-derived exosomal miR483-5p in hepatic stellate cell modulation

Toshio Miki

Shane Zhou MKK4/7 in JNK activation and hepatotoxicity Neil Kaplowitz

Yunheng Zhu

The inactivation of human HSCs and its implications for alcoholic liver disease therapy

David Brenner

Basic services Cell Bank

DirectorHide Tsukamoto

[email protected]

Research ScientistRaymond Wu

[email protected]

Financial AnalystAsma Deras

[email protected]

Lab SpecialistStephanie Pan

[email protected] Directors

Kinji [email protected]

Jun [email protected]

Our expert team

Special services. .

EducationAs part of its commitment to educating new investigators, andfacilitating collaboration among scientists in the �elds of ALPD, Cirrhosis and closely related biologies, the Center administers two educational programs at USC: The Lee Summer Research Fellowship and a graduate course, Pathology 575. The former program provides an opportunity for young students to work throughout the summer with Center Members who agree to serve as their mentors. Each student presents his/her work during the Center’s annual Progress Report meeting. Between 2013-2016, 31 students completed the Lee Summer Reserach Fellowship, earning a certi�cate and (where applicable) a cash award of $800. Forthe USC PATH 575 graduate course (entitled, the “Cellular Homeostasis Lecture Series”), which is entirely sponsored by the center,Center members are involved in hosting, coordinating, and lecturing on topics related to the Center’s themes. Between 2013-2016, 41 graduate students completed the course.

www.usc.edu/alpd 5

HAMID SAID, Center Associate Director for Education and Training, is a full Professor (above-scale)in the Departments of Medicine and Physiology/Biophysics of the University of California School of Medicine at Irvine. He holds a joint appointment with the Long Beach VA Medical Center as a Senior Research Career Scientist. Dr. Said did his postdoctoral research fellowship at the Scripps Clinic and Research Foundation in La Jolla, CA. In 1982 he joined the University of California School of Medicine at Irvine as a junior faculty. In 1984 he was recruited to the Vanderbilt Medical School in Nashville, TN, as an Assistant Professor, and returned to UCI in 1988 as an Associate Professor. He was promoted to a full Professor in 1994, and granted a tenure status in 2001.

The research of Dr. Said over the past thirty years has focused on studying the physiology and pathophysiology of water-soluble vitamin absorption/transport in organs of the digestive system. He has published seminal work in these areas and was the �rst to identify the existence of speci�c transport systems for many of these vitamins in a variety of epithelia, characterize their transcriptional

and post transcriptional regulation, and study the cell biology of the membrane transporters involved (i. e., membrane targeting/intracellular tra�cking). An example of the latter is his identi�cation of the existence of e�cient and speci�c carrier-mediated mechanisms for the absorption of many of the microbiota-generated water-soluble vitamins (e. g., biotin, thiamin, thiamin pyrophos-phate, ribo�avin, niacin, pyridoxine, and folate) in the human colon. Dr. Said has also been investigating the e�ect of exogenous/environmental factors that interfere with the absorption/transport of these essential micronutrients leading to de�ciency and sub-optimal levels, with a special focus on the e�ects of chronic alcohol use and chronic exposure to components of cigarette smoke. His studies have covered the entire spectrum of biological complexity from the whole (integrative) organism level, to intact tissues, isolated/cultured cells, sub-cellular organelle/components, to the molecular level, and have utilized state-of-the-art cellular, molecular, genetic and imaging approaches.


SPOTLIGHT ON: HAMID SAID, Ph.D., Pharm.D.


There were a total of 26 publications in the period from 2013-2016 by Pilot Project PI’s. Other career development outcomes of these PI’s include the following:A) Promotions 1) Shabnam Shalapour - From Project Scientist to Asst. Adjunct Professor

16 non-center investigators supported via

Tissue Sharing

19 grants acquired or applied

for by non-center investigators

supported by theAnimal Core

2013 - 201613 non-center investigators supported by

the Animal Core

www.usc.edu/alpd 2

Dr. Said’s research has been indepen-dently funded by the NIH/VA for over a quarter of a century. He currently holds the prestigious NIH MERIT Award for Consistent & Excellent Contributions to Scienti�c Knowledge (2009-2019), as well as the prestigious Senior Research Career Scientist Award from the DVA (1996-2022). He has received numerous awards, including the Horace W. Davenport Distinguished Award - the most prestigious award of the AmericanPhysiological Society (GI) (2012) in recognition of his distinguished lifetime achievement in GI and liver physiology.

AlcoholInhibits

Intestinal absorption

of WSV

Pancreatic uptakeof WSV

Liver uptakeof WSV

Vitamin deficiency/sub-optimal levels

Clinical Symptoms(anemia, neurological

disorder, cardiovascular disease, etc.)

Effect of chronic alcohol intake on physiology of water-soluble vitamins (WSV), and its consequence

1. Uthaya Kum

ar D. B., C

hen C.L., Liu J.C

., Feldman D

., Sher L.S., French S., DiN

orcia J., French S.W

., Naini B.V., Junrungsee S., Agopian V.G

., Zarrinpar A., Machida K. TLR

4 Signaling via N

ANO

G C

ooperates With STAT3 to Activate Tw

ist1 and Promote Form

ation of Tum

or-initiating Stem

-like C

ells in

Livers of

Mice.

2016 M

ar;150(3):707-19. doi:

10.1053/j.gastro.2015.11.002. Epub 2015 Nov 12. PM

ID: 26582088. PM

CID

: PMC

4766021. 2.

Mandrekar

P, Bataller

R,

Tsukamoto

H,

Gao

B. Alcoholic

hepatitis: Translational

approaches to develop targeted therapies. Hepatology. 2016 M

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ukherjee R, M

areninova OA, O

dinokova IV, Huang W

, Murphy J, C

hvanov M, Javed M

A, W

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, Cane M

C, Aw

ais M, G

avillet B, Pruss RM

, Schaller S, Molkentin JD

, Tepikin AV, Petersen O

H, Pandol SJ, G


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ukovskaya AS, Sutton R;

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5. Chen C

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ar DB, Punj V, X

u J, Sher L, Tahara SM, H

ess S, Machida K.

NAN

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eprograms Tum

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Physiol. 2016 Feb 15;310(4):G262-72. doi: 10.1152/ajpgi.00257.2015. Epub 2015 D

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hshiro K, Mistry N

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2) Jun Xu - From Postdoctoral Fellow to Asst. Project Scientist.B) Grant Applications, and Funded Non-Federal Grants 1) Jun Xu - NIH R01 grant application submitted. 2) Takeshi Saito - AMBRF grant application submitted. 3) Douglas Feldman - NIH R21 and R01 grant applications submitted. 4) Keane Lai - Wright Foundation Pilot Award funded, and Stop Cancer Seed grant received. 5) Akiko Eguchi - Kakenhi grant funded. 6) Ramachandran Murali - CTSI/CTRC pilot project funded. [CONTINUED ON NEXT PAGE]

23. Wang P, Koyama Y, Liu X, Xu J, Ma HY, Liang S, Kim IH, Brenner DA, Kisseleva T. Promising Therapy Candidates for Liver Fibrosis. Front Physiol. 2016 Feb 16;7:47. PMCID: PMC4754444. 24. Liang S, Kisseleva T, Brenner DA. The Role of NADPH Oxidases (NOXs) in Liver Fibrosis and the Activation of Myofibroblasts. Front Physiol. 2016 Feb 2;7:17. PMCID: PMC4735448. 25. Liu H, French SW. Mallory Denk Body Formation in Alcoholic Hepatitis: The Pivotal Role of Interleukin-8 Signaling. Clin Microbiol. 2016 Feb;5(1). pii: 235. PMCID: PMC4807866. 26. Prieto-Domínguez N, Ordóñez R, Fernández A, Méndez-Blanco C, Baulies A, Garcia-Ruiz C, Fernández-Checa JC, Mauriz JL, González-Gallego J. Melatonin-induced increase in sensitivity of human hepatocellular carcinoma cells to sorafenib is associated with reactive oxygen species production and mitophagy. J Pineal Res. 2016 Oct;61(3):396-407. PMCID: PMC5018464. 27. Ribas V, García-Ruiz C, Fernández-Checa JC. Mitochondria, cholesterol and cancer cell metabolism. Clin Transl Med. 2016 Dec;5(1):22. PMCID: PMC4960093. 28. Stefanovic M, Tutusaus A, Martinez-Nieto GA, Bárcena C, de Gregorio E, Moutinho C, Barbero-Camps E, Villanueva A, Colell A, Marí M, García-Ruiz C, Fernandez-Checa JC, Morales A. Targeting glucosylceramide synthase upregulation reverts sorafenib resistance in experimental hepatocellular carcinoma. Oncotarget. 2016 Feb 16;7(7):8253-67. PMCID: PMC4884990. 29. Eguchi A, Lazaro, R, Wang J, Kim J, Povero D, Willliams B, Ho S, Stärkel P, Schnabl B, Ohno-Machado L, Tsukamoto H, Feldstein AE . Extracellular vesicles released by hepatocytes from gastric infusion model of ALD contain a miRNA barcode that can be detected in blood. Hepatology. 2016 Sep 17. PMID: 27639178. 30. Valente, T., Sidhu, A., Lee, J., Baezconde-Garbanati, L., Pandol, S., Saab, S., Mendler, M., Tsukamoto, H. Lagged versus Difference score regression: An example from a community based educational seminar evaluation. Pedagogy in Health Promotion. (In Press). ** 31. Wang L, Fouts DE, Stärkel P, Hartmann P, Chen P, Llorente C, DePew J, Moncera K, Ho SB, Brenner DA, Hooper LV, Schnabl B. Intestinal REG3 Lectins Protect Against Alcoholic Steatohepatitis by Reducing Mucosa-associated Microbiota and Preventing Bacterial Translocation. Cell Host Microbe. 2016 Feb 10;19(2):227-39. PMCID: PMC4786170. 32. French SW. Chronic alcohol binging injures the liver and other organs by reducing NAD⁺ levels required for sirtuin's deacetylase activity. Exp Mol Pathol. 2016 Apr;100(2):303-6. PMID: 26896648. 33. Bluemel S, Williams B, Knight R, Schnabl B. Precision Medicine in Alcoholic and Non-Alcoholic Fatty Liver Disease via Modulating the Gut Microbiota. Am J Physiol Gastrointest Liver Physiol. 2016 Sep 29:ajpgi.00245.2016. PMID: 27686615. 34. Ho SB, Matheny M, Schnabl B. Changes in hospital admissions and mortality for complications of cirrhosis: implications for clinicians and health systems. Gut Liver. 2016 Jan;10(1):8-9. PMCID: PMC4694728. 35. Nakamoto N, Schnabl B. Does the intestinal microbiota explain differences in the epidemiology of liver disease between East and West? Inflamm Intest Dis. 2016 Apr;1(1):3-8. PMCID: PMC4883108. 36. Schnabl B. Liver Capsule: Mechanisms of Alcoholic Hepatitis. Hepatology. 2016 Jul;64(1):276. PMID: 26867027. 37. Fuchs M, Schnabl B. Editors' Introduction to the NAFLD and NASH Special Issue. Dig Dis Sci. 2016 May;61(5):1211-3. PMID: 27068170. 38. Arroyo V, Moreau R, Kamath PS, Jalan R, Gines P, Nevens F, Fernandez J, To U, Garcia-Tsao G, Schnabl B. Acute-on-chronic liver failure in cirrhosis. Nat Rev Dis Primers. 2016 Jun 9;2:16041. PMID: 27277335. 39. Chen P, Miyamoto Y, Mazagova M, Lee K, Eckmann L, Schnabl B. Microbiota and Alcoholic Liver Disease. Alcohol Clin Exp Res. 2016 Aug;40(8):1791-2. PMID: 27364225. 40. Llorente C, Schnabl B. Fast-track clearance of bacteria from the liver. Cell Host Microbe. 2016 Jul 13;20(1):1-2. PMID: 27414492. 41. He L, Gubbins J, Peng Z, Medina V, Fei F, Asahina K, Wang J, Kahn M, Rountree CB, Stiles BL. Activation of hepatic stellate cell in Pten null liver injury model. Fibrogenesis Tissue Repair. 2016 Jun 14;9:8. PMCID: PMC4908727. 42. DeLeve LD, Wang X, Wang L. VEGF-sdf1 recruitment of CXCR7+ bone marrow progenitors of liver sinusoidal endothelial cells promotes rat liver regeneration. Am J Physiol Gastrointest Liver Physiol. 2016 May 1;310(9):G739-46. PMCID: PMC4867332. 43. Pham H, Birtolo C, Chheda C, Yang W, Rodriguez MD, Liu ST, Gugliotta G, Lewis MS, Cirulli V, Pandol SJ, Ptasznik A. Essential Role of Lyn in Fibrosis. Front Physiol. 2016 Aug 31;7:387. PMCID: PMC5006658. 44. Setiawan VW, Pandol SJ, Porcel J, Wei PC, Wilkens LR, Le Marchand L, Pike MC, Monroe KR. Dietary Factors Reduce Risk of Acute Pancreatitis in a Large Multiethnic Cohort. Clin Gastroenterol Hepatol. 2016 Sep 5. pii: S1542-3565(16)30619-X. PMID: 27609706. 45. Chen C.L., Huang, J., Wang, J., Zhou L., Kondo, Y., Schechter J., Su L., Lai M.M., Wakita, T., Cosset F.L., Jung. J., Machida K., Memory B cells are infected with lymphotropic hepatitis C virus through novel co-receptor B7.2, Nature Communications, Accepted, 2016. 46. Ma HY, Xu J, Liu X, Zhu Y, Gao B, Karin M, Tsukamoto H, Jeste DV, Grant I, Roberts AJ, Contet C, Geoffroy C, Zheng B, Brenner D, Kisseleva T. The role of IL-17 signaling in regulation of the liver-brain axis and intestinal permeability in Alcoholic Liver Disease. Curr Pathobiol Rep. 2016 Mar;4(1):27-35. PMCID: PMC4878828. 47. Chen S, Kang Y, Sun Y, Zhong Y, Li Y, Deng L, Tao J, Li Y, Tian Y, Zhao Y, Cheng J, Liu W, Feng GS, Lu Z. Deletion of Gab2 in mice protects against hepatic steatosis and steatohepatitis: a novel therapeutic target for fatty liver disease. J Mol Cell Biol. 2016 Jun 9. PMID: 27282405. 48. Nuño-Lámbarri N, Domínguez-Pérez M, Baulies-Domenech A, Monte MJ, Marin JJ, Rosales-Cruz P, Souza V, Miranda RU, Bucio L, Montalvo-Jave EE, Concepción Gutiérrez-Ruiz M, García-Ruiz C, Fernández-Checa JC, Gomez-Quiroz LE. Liver Cholesterol Overload Aggravates Obstructive Cholestasis by Inducing Oxidative Stress and Premature Death in Mice. Oxid Med Cell Longev. 2016;2016:9895176. PMCID: PMC5011220. 49. Gao B, Tsukamoto H. Inflammation in Alcoholic and Nonalcoholic Fatty Liver Disease: Friend or Foe? Gastroenterology. 2016 Jun;150(8):1704-9. PMCID: PMC4887345. 50. Kim IH, Xu J, Liu X, Koyama Y, Ma HY, Diggle K, You YH, Schilling JM, Jeste D, Sharma K, Brenner DA, Kisseleva T. Aging increases the susceptibility of hepatic inflammation, liver fibrosis and aging in response to high-fat diet in mice. Age (Dordr). 2016 Aug 30. PMCID: PMC5061686. 51. Harrall KK, Kechris KJ, Tabakoff B, Hoffman PL, Hines LM, Tsukamoto H, Pravenec M, Printz M, Saba LM. Uncovering the liver's role in immunity through RNA co-expression networks. Mamm Genome. 2016 Oct;27(9-10):469-84. PMCID: PMC5002042.

** Director’s selected highlights

1. Uthaya Kumar D. B., Chen C.L., Liu J.C., Feldman D., Sher L.S., French S., DiNorcia J., French S.W., Naini B.V., Junrungsee S., Agopian V.G., Zarrinpar A., Machida K. TLR4 Signaling via NANOG Cooperates With STAT3 to Activate Twist1 and Promote Formation of Tumor-initiating Stem-like Cells in Livers of Mice. Gastroenterology. 2016 Mar;150(3):707-19. PMCID: PMC4766021. 2. Mandrekar P, Bataller R, Tsukamoto H, Gao B. Alcoholic hepatitis: Translational approaches to develop targeted therapies. Hepatology. 2016 Mar 3. PMCID: PMC5010788. 3. Mukherjee R, Mareninova OA, Odinokova IV, Huang W, Murphy J, Chvanov M, Javed MA, Wen L, Booth DM, Cane MC, Awais M, Gavillet B, Pruss RM, Schaller S, Molkentin JD, Tepikin AV, Petersen OH, Pandol SJ, Gukovsky I, Criddle DN, Gukovskaya AS, Sutton R; NIHR Pancreas Biomedical Research Unit.Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: inhibition prevents acute pancreatitis by protecting production of ATP. Gut. 2016 Aug;65(8):1333-46. PMCID: PMC4920725. 4. Avila DV, Barker DF, Zhang J, McClain CJ, Barve S, Gobejishvili L. Dysregulation of hepatic cAMP levels via altered Pde4b expression plays a critical role in alcohol-induced steatosis. J Pathol. 2016 Jun 11. PMCID: PMC4993672. ** 5. Chen CL, Uthaya Kumar DB, Punj V, Xu J, Sher L, Tahara SM, Hess S, Machida K. NANOG Metabolically Reprograms Tumor-Initiating Stem-like Cells through Tumorigenic Changes in Oxidative Phosphorylation and Fatty Acid Metabolism. Cell Metab. 2016 Jan 12;23(1):206-19. PMCID: PMC4715587. 6. Li Y, Lua I, French SW, Asahina K. Role of TGF-β signaling in differentiation of mesothelial cells to vitamin A-poor hepatic stellate cells in liver fibrosis. Am J Physiol Gastrointest Liver Physiol. 2016 Feb 15;310(4):G262-72. PMCID: PMC4754741. 7. Puri P, Xu J, Vihervaara T, Katainen R, Ekroos K, Daita K, Min HK, Joyce A, Mirshahi F, Tsukamoto H, Sanyal AJ. Alcohol produces distinct hepatic lipidome and eicosanoid signature in lean and obese. J Lipid Res. 2016 Jun;57(6):1017-28. PMCID: PMC4878186. 8. Kweon SM, Chi F, Higashiyama R, Lai K, Tsukamoto H. Wnt Pathway Stabilizes MeCP2 Protein to Repress PPAR-γ in Activation of Hepatic Stellate Cells. PLoS One. 2016 May 23;11(5):e0156111. PMCID: PMC4877088. 9. Chen J, Yao ZX, Chen JS, Gi YJ, Muñoz NM, Kundra S, Herlong HF, Jeong YS, Goltsov A, Ohshiro K, Mistry NA, Zhang J, Su X, Choufani S, Mitra A, Li S, Mishra B, White J, Rashid A, Wang AY, Javle M, Davila M, Michaely P, Weksberg R, Hofstetter WL, Finegold MJ, Shay JW, Machida K, Tsukamoto H, Mishra L. TGF-β/β2-spectrin/CTCF-regulated tumor suppression in human stem cell disorder Beckwith-Wiedemann syndrome. J Clin Invest. 2016 Feb;126(2):527-42. PMCID: PMC4731168. 10. Lua I, Asahina K. The Role of Mesothelial Cells in Liver Development, Injury, and Regeneration. Gut Liver. 2016 Mar;10(2):166-76. PMCID: PMC4780447. ** 11. Lua I, Li Y, Zagory JA, Wang KS, French SW, Sévigny J, Asahina K. Characterization of hepatic stellate cells, portal fibroblasts, and mesothelial cells in normal and fibrotic livers. J Hepatol. 2016 May;64(5):1137-46. PMCID: PMC4834254. ** 12. Cho NE, Bang BR, Gurung P, Li M, Clemens DL, Underhill TM, James LP, Chase JR, Saito T. Retinoid regulation of antiviral innate immunity in hepatocytes. Hepatology. 2016 Jun;63(6):1783-95. PMCID: PMC4874888. 13. Habtezion A, Edderkaoui M, Pandol SJ. Macrophages and pancreatic ductal adenocarcinoma. Cancer Lett. 2015 Dec 18. pii: S0304-3835(15)00746-6. PMCID: PMC4912945. 14. Edderkaoui M, Xu S, Chheda C, Morvaridi S, Hu RW, Grippo PJ, Mascariñas E, Principe DR, Knudsen B, Xue J, Habtezion A, Uyeminami D, Pinkerton KE, Pandol SJ. HDAC3 mediates smoking-induced pancreatic cancer. Oncotarget. 2016 Feb 16;7(7):7747-60. PMCID: PMC4884951. 15. Gukovskaya AS, Pandol SJ, Gukovsky I. New insights into the pathways initiating and driving pancreatitis.Curr Opin Gastroenterol. 2016 Jul 13. PMID: 27428704. ** 16. Su HY, Waldron RT, Gong R, Ramanujan VK, Pandol SJ, Lugea A. The Unfolded Protein Response Plays a Predominant Homeostatic Role in Response to Mitochondrial Stress in Pancreatic Stellate Cells. PLoS One. 2016 Feb 5;11(2):e0148999. PMCID: PMC4743835. 17. Setiawan VW, Pandol SJ, Porcel J, Wilkens LR, Le Marchand L, Pike MC, Monroe KR. Prospective Study of Alcohol Drinking, Smoking, and Pancreatitis: The Multiethnic Cohort. Pancreas. 2016 Jul;45(6):819-25. PMCID: PMC4905778. 18. Quinn BA, Wang S, Barile E, Das SK, Emdad L, Sarkar D, De SK, Morvaridi SK, Stebbins JL, Pandol SJ, Fisher PB, Pellecchia M. Therapy of pancreatic cancer via an EphA2 receptor-targeted delivery of gemcitabine. Oncotarget. 2016 Mar 29;7(13):17103-10. PMCID: PMC4941374. 19. Birtolo C, Go VL, Ptasznik A, Eibl G, Pandol SJ. Phosphatidylinositol 3-Kinase: A Link Between Inflammation and Pancreatic Cancer. Pancreas. 2016 Jan;45(1):21-31. PMCID: PMC4859755. 20. Subramanian VS, Srinivasan P, Said HM. Uptake of ascorbic acid by pancreatic acinar cells is negatively impacted by chronic alcohol exposure. Am J Physiol Cell Physiol. 2016 Jul 1;311(1):C129-35. PMCID: PMC4967129. 21. Yuan J, Pandol SJ. PKD signaling and pancreatitis. J Gastroenterol. 2016 Jul;51(7):651-9. PMCID: PMC4921304. 22. Koyama Y, Xu J, Liu X, Brenner DA. New Developments on the Treatment of Liver Fibrosis. Dig Dis. 2016;34(5):589-96. PMCID: PMC4961096.

PI/P

D

Gran

t Num

ber

Title / Project P

eriod / A

nn

ual DC

Asahina, K

inji 1R

21AA

024840-01

DIS

SE

CT

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OF

GLIS

SO

N'S

CA

PS

ULE

IN

ALC

OH

OL IN

DU

CE

D LIV

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INJU

RY

. [8/20/16-7/31/18; $143,750]

Kum

ar, Vipin

5R01A

A020864-

06

INT

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PLA

Y A

MO

NG

NK

T C

ELL S

UB

SE

TS

IN

ALC

OH

OLIC

LIVE

R D

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AS

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$222,500]

Lugea, A

urelia 1R

01AA

019954-06

ALC

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AN

D E

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OP

LAS

MIC

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LUM

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SF

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IN E

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Pandol,

Stephen

1R01A

A024464-

01A1

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PR

OT

EIN

KIN

AS

E D

IN A

LCO

HO

LIC

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AT

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[9/1/16-6/30/21; $225,000]

Schnabl,

Bernd

5R01A

A020703-

06A

MIC

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[9/25/11-6/30/21; $225,000] T

sukamoto,

Hidekazu

2R24A

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GR

AT

IVE

LIVE

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sukamoto,

Hidekazu

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LPD

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PI/PD Grant Number Title / Project Period / Annual DC


DISSECTION OF GLISSON'S CAPSULE IN ALCOHOL INDUCED LIVER INJURY. [8/20/16-7/31/18; $143,750]

Pandol, Stephen

1R01AA024464-01A1

TARGETING PROTEIN KINASE D IN ALCOHOLIC PANCREATITIS [9/1/16-6/30/21; $225,000]

Schnabl, Bernd

5R01AA020703-06A

MICROBIOME AND INTESTINAL INNATE IMMUNE RESPONSE IN ALCOHOLIC LIVER DISEASE [9/25/11-6/30/21; $225,000]

Tsukamoto, Hidekazu

2R24AA012885-16

INTEGRATIVE LIVER CELL CORE [6/1/01-5/31/21; $292,743]

Tsukamoto, Hidekazu

5R13AA020691-06

INTERNATIONAL SYMPOSIUM ON ALPD AND CIRRHOSIS [8/5/11-4/30/21; $50,000]

RECENT GRANTS AND PUBLICATIONS (2016)BY CENTER MEMBERS


www.usc.edu/alpd



CONTACTSHidekazu Tsukamoto

Director

[email protected]

323-442-5107

Asma Deras

Business/Budget [email protected]

Fax: 323-442-3126

www.usc.edu/alpd

Program Administrator (2015-2016) and Newsletter Editor:Sean Kohlmeier

Our Center which is supported by a NIAAA P50 grant is a multi-component program encompassing Administrative Core, Animal Core, Morphology Corefour distinct Research Projects, and a Pilot Project program. In its 18th year,the Center has begun its self-evaluation. To perform this task, the productivity of each Center component must �rst be carefully evaluated. To this end, the Center’s External Advisory Board has been asked to “peer-review” the data generated by each component during the past four years . The independent and critical review provided by the External Advisory Board and its valuable feedback, are essential for the Center’s self-assessment and its future programmatic devolopment. The following summarizes the overall state of the Center and activities of AnimalCore which truly is the center’s epicenter unifying the cener members, catalyzing collaborations, and serving as an pivotal national resource for investigators in the �eld of alcoholic liver and pancreatic diseases, cirrhosis, liver and pancreatic cancer across the nation.




R24 AA012885 and R13 AA020691.

INSIDE THIS ISSUE

1 Evaluation of Center’s Components

2 Spotlight on Dr. Hamid Said

3 The Integrative Liver Cell Core Renwal

4 New Animal Core Model: Patient-Derived Xenograft

4 11th International Symposium on ALPD/C

4 Lee Summer ResearchFellowship Program

5 Recent Grants andPublications (2016)by Center Members

Who are the Center’sExternal AdvisoryBoard Members?

Dr. Ramon Bataller

Dr. Bin Gao

Dr. Vijay Shah

Dr. Laura Nagy

Dr. Nicholas Davidson

Dr. Gyongyi Szabo

Dr. Ashok Saluja

Numbers at Glance for 2013-2016:

Center as a whole:

• 64 center members from 59 in 2013• $14.1M research base (direct costs) of which $7M from NIAAA• 185 publications of which 43% collaborative papers

The Animal Core supported in the last 4 years:

• 2486 models produced based on 19 di�erent model versions• 22 center members • 56 publications by center members • 35 collaborative papers • 25 grants acquired/applied by the center members • 13 non-center investigators • 4 publications by non-center members• 15 grants acquired/applied by non-center investigators• 430 samples shared by 16 non-center investigators via Tissur Sharing Program

Pilot Project Program OutcomeA total of 16 Pilot Projects were funded by the Center between 2013 and 2016, with $319,000 in funds distributed for the program. The outcomes during this grant cycle are notable, with the following NIH grants acquired by Pilot Project alumni: K01AA020524 (PI: Jun Xu), R21AA022751 (PI: Takeshi Saito),R01DK101773 (PI: Takeshi Saito), R21AA023574 (PI: Akiko Eguchi),K08AA025112 (PI: Keane Lai - pending).

[CONTINUED ON NEXT PAGE]

Hiekazu TsukamotoCenter Director

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