RIKEN Center for Life Science Technologies

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Labs & Technologies

Micro-Signaling Regulation Technology Unit

Studies on Molecular Cellular Pathology and Control of Liver Diseases

Unit Leader
Soichi Kojima  Ph.D.

408 Main Research Building, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
Tel: +81-48-467-7938

3_10_kojima.png

Research Area

Research Experience (itemized)

 “Clarification of Pathogenesis and Drug Discovery toward Hepatic Diseases” 

Identification of novel micro-signals (targets for drug discovery) in liver diseases and high throughput screening of their regulatory compounds for future drug discovery utilizing chemical biology techniques. 

1.   Screening of Novel Drugs: Drug discovery and development of new drugs (non- nucleotide analogues) against hepatitis B virus (HBV) utilizing the next generation life science technologies under financial support from AMED.

2.   Development of New Diagnosis Method: Development of diagnosis, prevention, and therapy against early stage of liver fibrosis targeting novel liver fibrogenesis marker, TGF- LAP-DP under collaboration with medical universities and companies.

3.   Molecular Mechanism of Novel Drugs: Studies on nuclear TG2/crosslinking and inactivation of Sp1/selective apoptosis of MYCN positive liver cancer stem cells by phase III drug candidate, acyclic retinoid (Peretinoin) and their control by foods.

 

Perspectives

 Continue collaboration with medical universities and companies within Japan and worldwide for basic and applied researches on establishment of novel diagnosis, prevention, and therapy against hepatitis aiming to start translational researches. 

1.   Screening of Novel Drugs against HBV: Under financial support from AMED, identify the target protein and downstream molecular mechanisms of the candidate compounds, analyze target-compound interaction using NMR/Spring 8, and based on obtained information perform in silico screening with Kei computer, getting the lead compounds. After ADMET and animal experiments, find a partner companies, and start Phase I clinical trials.

2.   Development of New Diagnosis for Liver Fibrogenesis Targeting TGF- LAP-DP: Develop the diagnosis kit by collaborating with Jikei Med Univ and the diagnosis company S, aim to establish a PET imaging of tissue fibrogenesis with labeled anti- LAP-DP antibodies, and using these techniques challenge to develop anti-fibrotic drugs under collaboration with the S Pharm.

3.   Molecular Mechanism of Novel Drugs Killing Selectively Liver Cancer Stem Cells: Under collaboration with K Pharm, perform global analyses including every OMICs and elucidate whole figure of the molecular mechanism, start single cell analyses based on the result of the big data analyses aiming to personalized medicine, and continue collaboration to find novel food component under collaborations. 

Main Publications List

1

Metabolome analyses uncovered a novel inhibitory effect of acyclic retinoid on aberrant lipogenesis in a mouse diethylnitrosamine-induced hepatic tumorigenesis model

Qin XY, Tatsukawa H, Hitomi K, Shirakami Y, Ishibashi N, Shimizu M, Moriwaki H, Kojima S
Cancer Prev Res (Selected for the cover page image), 9(3), 205-214 (2016).
2

Molecular mechanism by which acyclic retinoid induces nuclear localization of transglutaminase 2 in human hepatocellular carcinoma cells

Shrestha R, Tatsukawa H, Shrestha R, Ishibashi N, Matsuura T, Kagechika H, Kose S, Hitomi K, Imamoto N, Kojima S
Cell Death Dis., 6(12), e2002 (2015).
3

L(59) TGF-β LAP degradation products serve as a promising blood biomarker for liver fibrogenesis in mice.

Hara M, Inoue I, Yamazaki Y, Kirita A, Matsuura T, Friedman SL, Rifkin DB, Kojima S
Fibrogenesis Tissue Repair., 8(17), (2015).
4

Dysregulation of Retinoic Acid Receptor Diminishes Hepatocyte Permissiveness to Hepatitis B Virus Infection through Modulation of Sodium Taurocholate Cotransporting Polypeptide (NTCP) Expression.

Tsukuda S, Watashi K, Iwamoto M, Suzuki R, Aizaki H, Okada M, Sugiyama M, Kojima S, Tanaka Y, Mizokami M, Li J, Tong S, Wakita T.
J Biol Chem, 290(9), 5673-5684 (2015).
5

LAP degradation product reflects plasma kallikrein-dependent TGF-β activation in patients with hepatic fibrosis.

Hara M, Kirita A, Kondo W, Matsuura T, Nagatsuma K, Dohmae N, Ogawa S, Imajoh-Ohmi S, Friedman SL, Rifkin DB, Kojima S.
Springerplus, 3, 221 (2014).
6

The Effect of Acyclic Retinoid on the Metabolomic Profiles of Hepatocytes and Hepatocellular Carcinoma Cells

Qin XY, Wei F, Tanokura M, Ishibashi N, Shimizu M, Moriwaki H, Kojima S.
PLoS One, 8(12), e82860 (2013).
7

HCV NS3 protease enhances liver fibrosis via binding to and activating TGF-β type I receptor

Sakata K, Hara M, Terada T, Watanabe N, Takaya D, Yaguchi S, Matsumoto T, Matsuura T, Shirouzu M, Yokoyama S, Yamaguchi T, Miyazawa K, Aizaki H, Suzuki T, Wakita T, Imoto M, Kojima S.
Sci Rep, 3, 3243 (2013).
8

Free fatty acids induce transglutaminase 2-dependent apoptosis in hepatocytes via ER stress-stimulated PERK pathways.

Kuo TF, Tatsukawa H, Matsuura T, Nagatsuma K, Hirose S, Kojima S.
J Cell Physiol, 227(3), 1130-1137 (2012).
9

Dual induction of caspase 3- and transglutaminase-dependent apoptosis by acyclic retinoid in hepatocellular carcinoma cells.

Tatsukawa H, Sano T, Fukaya Y, Ishibashi N, Watanabe M, Okuno M, Moriwaki H, Kojima S.
Mol Cancer, 10, 4 (2011).
10

Role of transglutaminase 2 in liver injury via cross-linking and silencing of transcription factor Sp1.

Tatsukawa H, Fukaya Y, Frampton G, Martinez-Fuentes A, Suzuki K, Kuo TF, Nagatsuma K, Shimokado K, Okuno M, Wu J, Iismaa S, Matsuura T, Tsukamoto H, Zern MA, Graham RM, Kojima S.
Gastroenterology, 136(5), 1783-1795 (2009).

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