Study on the function of a novel inflammatorymarker protein(LRG) in the pathogenes I s of autoimmune d I sorders

2012 Fiscal Year Final Research Report

• Project/Area Number: 22591101
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: 独立行政法人医薬基盤研究所
• Principal Investigator: NAKA Tetsuji 独立行政法人医薬基盤研究所, 創薬基盤研究部, 部長 (30303936)
• Project Period (FY): 2010 – 2012
• Keywords: 臨床免疫学

Research Abstract

The uncharacterized function of LRG, a novel biomarker for autoimmune disorders, was investigated in this study. By proteomics approach and two-hybrid screening, several candidates of LRG-interacting proteins including possible receptors have been identified. Generation and analysis of LRG knockout mice have revealed that LRG is dispensable for the survival of mice, but is involved in the progression of several immune diseases. The results suggest that LRG is a promising target of immune disorders. Further studies on LRG as a potential therapeutic target will be on the way in collaboration with a pharmaceutical company.

Research Products

• [Journal Article] Lectin-based immunoassay for aberrant IgG glycosylation as the biomarker for Crohn's disease (2013)
  • Author(s): Shinzaki S, Kuroki E, Iijima H, Tatsunaka N, Ishii M, Fujii H, Kamada Y, Kobayashi T, Shibukawa N, Inoue T, Tsujii M, Takeishi S, Mizushima T, Ogata A, Naka T, Plevy SE, Takehara T, Miyoshi E
  • Journal Title: Inflamm Bowel Dis Volume: 19(2) Pages: 321-31
  • DOI: DOI:10.1097/MIB. ObO13e318280eade
  • Peer Reviewed
• [Journal Article] Plasma nlembrane proteonlics identifies bone marrow stromal antigen 2 as a potential therapeutic target in endometrial cancer (2013)
  • Author(s): Yokoyama T, Enomoto T, Serada S, Morimoto A, Matsuzaki S, Ueda Y, Yoshino K, Fujita M, Kyo S, Iwahori K, Fujimoto M, Kimura T, Naka T
  • Journal Title: Int J Cancer Volume: 132(2) Pages: 472-84
  • DOI: Dol:10.1002/ijc.27679
  • Peer Reviewed
• [Journal Article] SOCS-1 gene delivery cooperates with cisplatin plus pemetrexed to exhibit preclinical antitUmor activity against malignant pleural mesothelioma (2013)
  • Author(s): Iwahori K, Serada S, Fujimoto M, Ripley B, Nomura S, Mizuguchi H, Shimada S, Takahashi T, Kawase I, Kishimoto T, Naka T
  • Journal Title: Int J Cancer Volume: 132(2) Pages: 459-71
  • DOI: Dol:10.1002/ijc.27611
  • Peer Reviewed
• [Journal Article] Adoptive transfer of Th1-conditioned lymphocytes promotes axonal remodeling and functional recovery after spinal cord lnJury (2012)
  • Author(s): Ishii H, Jin X, Ueno M, Tanabe S, Kubo, Serada S, Naka T. Yamashita T
  • Journal Title: Cell Death Dis Volume: 3 Pages: e363
  • DOI: DOI:10.1038/cddis.2012.106
  • Peer Reviewed
• [Journal Article] Serum HE4 as a diagnostic and prognostic marker for lung cancer (2012)
  • Author(s): Iwahori K, Suzuki H, Kishi Y, Fujii Y, Uehara R, Okamoto N, Kobayashi M, Hirashima T, Kawase I, Naka T
  • Journal Title: Tumour Biol Volume: 33(4) Pages: 1141-9
  • DOI: DOI:10.1007/s13277-012-0356-9
  • Peer Reviewed
• [Journal Article] Suppressor of cytokine signaling l DNA administration inhibits inflammatory and pathogenic responses in autoimmune myocarditis (2012)
  • Author(s): Tajiri K, Imanaka-Yoshida K, Matsubara A, Tsujimura Y, Hiroe M, Naka T, Shimojo N, Sakai S, Aonuma K, Yasutomi Y
  • Journal Title: J Immunol Volume: 189(4) Pages: 2043-53
  • DOI: DOI:10.4049/jimmunol.1103610
  • Peer Reviewed
• [Journal Article] Involvement of SIK3 in glucose and lipid homeostasis in mice (2012)
  • Author(s): Uebi T, Itoh Y, Hatano O, Kumagai A, Sanosaka M, Sasaki T, Sasagawa S, Doi J, Tatsumi K, Mitanlura K, Morii E, Aozasa K, Kawamura T, Okumura M, Nakae J, Takikawa H, Fukusato T, Koura M, Nish M, Hamsten A, Silveira A, Bertorello A M, Kitagawa K, Nagaoka Y, Kawahara H, Tomonaga T, Naka T, Ikegawa S, Tsumaki N, Matsuda J, Takemori H
  • Journal Title: PLoS One Volume: 7(5) Pages: e37803
  • DOI: DOI:10.1371/journal.pone.0037803
  • Peer Reviewed
• [Journal Article] Periostin Facilitates Skin Sclerosis via PI3K/Akt Dependent Mechanism in a Mouse Model of Scleroderma (2012)
  • Author(s): Yang L, Serada S, Fujimoto M, Terao M, Kotobuki Y, Kitaba S, Matsui S, Kudo A, Naka T, Murota H, Katayama I
  • Journal Title: PLoS One Volume: 7(7) Pages: e41994
  • DOI: DOI:10.1371/journal.pone.0041994
  • Peer Reviewed
• [Journal Article] Serum leucine-rich alpha-2 glycoprotein is a disease activity biomarker in UICeratiVe COIitiS (2012)
  • Author(s): Serada S, Fujimoto M, Terabe F, Iijima H, Shinzaki S, Matsuzaki S, Ohkawara T, Nezu R, Nakajima S, Kobayashi T, Plevy SE, Takehara T, Naka T
  • Journal Title: Inflamm Bowel Dis Volume: 18(11) Pages: 2169-79
  • DOI: doi:10.1002/ibd.22936.
  • Peer Reviewed
• [Journal Article] Dysregulation of Melanocyte Function by Th17-related Cytokines: Significance of Th17 Cell Infiltration in Autoimmune Vitiligo Vulgaris (2012)
  • Author(s): Kotobuki Y, Tanemura A, Yang L, Itoi S, Kaneda M, Murota H, Fujimoto M, Serada S, Naka T Katayama I
  • Journal Title: Pigment Cell Melanonla Res Volume: 25(2) Pages: 219-30
  • DOI: DOI:10.1111/j.1755-148X.2011.00945
  • Peer Reviewed
• [Journal Article] Anti-proliferative effect of SOCS-1 through the suppression of STAT3 and p38 MAPK activation in gastric cancer cells (2012)
  • Author(s): Souma Y, Nishida T, Serada S, Iwahori K, Takahashi T, Fujimoto M, Ripley B, Nakajima K, Miyazaki Y, Mori M, Doki Y, Sawa Y, Naka T
  • Journal Title: Int J Cancer Volume: 131(6) Pages: 1287-96
  • DOI: Dol:10.1002/ijc.27350
  • Peer Reviewed
• [Journal Article] Periostin, a matricellular protein, accelerates cutaneous wound repair by activating dermal fibroblasts (2012)
  • Author(s): Ontsuka K, Kotobuki Y, Shiraishi H, Serada S, Ohta S, Tanenlura A, Yang L, Fujimoto M, Arima K, Suzuki S, Murota H, Toda S, Kudo A, Conway S, Narisawa Y,Katayama I, Izuhara K, Naka T
  • Journal Title: Exp Dermatol Volume: 21(5) Pages: 331-336
  • DOI: DOI:10.1111/j.1600-0625.2012.01454.
  • Peer Reviewed
• [Journal Article] Blockade of interleukin-6 receptor alleviates disease in mouse model of scleroderma (2012)
  • Author(s): Kitaba S, Murota H, Terao M, Azukizawa H, Terabe F, Shima Y, Fujimoto M, Tanaka T, Naka T, Kishimoto T, Katayama I
  • Journal Title: Am J Pathol Volume: 180(1) Pages: 165-76
  • DOI: DOI:10.1016/j. ajpath.2011.09.013
  • Peer Reviewed
• [Journal Article] IL-6によるレギュラトリーT細胞の抑制:nTregとiTregの相違 (2012)
  • Author(s): 藤本 穣、寺部 文隆、仲 哲治
  • Journal Title: 臨床免疫・アレルギー科 Volume: 57(1) Pages: 79-86
• [Journal Article] IL-6-mediated h17 differentiation through RORgammat is essential for the initiation of experimental autoimmune myocarditis (2011)
  • Author(s): Yamashita T, Iwakura T, Matsui K, Kawaguchi H, Obana M, Hayanla A, Maeda M, Izumi Y, Komuro I, Ohsugi Y, Fuj imoto M, Naka T, Kishimoto T, Nakayama H, Fujio Y
  • Journal Title: Cardiovasc Res Volume: 91(4) Pages: 640-8
  • DOI: DOI:10.1093/cvr/cvr148
  • Peer Reviewed
• [Journal Article] Blockade of interleukin-6 signaling suppresses not only th17 but also interphotoreceptor retinoid binding protein-specific Thl by promotin regulatory T cells in experimental autoimmune uveoretinitis (2011)
  • Author(s): Haruta H, Ohguro N, Fujimoto M, Hohki S, Terabe F, Serada S, Nomura S, Nishida K, Kishimoto T, Naka T
  • Journal Title: Invest Ophthalmol Vis Sci Volume: 52(6) Pages: 3264-71
  • DOI: DOI:10.1167/iovs.10-6272
  • Peer Reviewed
• [Journal Article] The Influence of Excessive IL-6 Production In Vivo on the Development and Function of Foxp3+ Regulatory T Cells (2011)
  • Author(s): Fujimoto M, Nakano M, Terabe F, Kawahata H, Ohkawara T, Han Y, Ripley B, Serada S, Nishikawa T, Kimura A, Nonlura S, Kishimoto T, Naka T
  • Journal Title: J Immunol Volume: 186(1) Pages: 32-40
  • DOI: DOI:10.4049/jimmunol.0903314
  • Peer Reviewed
• [Journal Article] Overexpression of SOCS3 exhibits preclinical antitumor activity against malignant pleural mesothelioma (2011)
  • Author(s): Iwahori K, Serada S, Fujimoto M, Nomura S, Osaki T, Chun Man Lee, Mizuguchi H, Takahashi T, Ripley B, Okumura M, Kawase I, Kishimoto T, Naka T
  • Journal Title: Int J Cancer Volume: 129(4) Pages: 1005-17
  • DOI: Dol:10.1002/ijc.25716
  • Peer Reviewed
• [Journal Article] Comparative analysis of the effects of anti-IL-6 receptor mAb and anti-TNF mAb treatment on CD4+ T-cell responses in murine colitis (2011)
  • Author(s): Terabe F, Fujimoto M, Serada S, Shinzaki S, Iijima H, Tsujii M, Hayashi N, Nomura S, Kawahata H, Myoung Ho Jang, Miyasaka M, Mihara M, Ohsugi Y, Kishimoto T, Naka T
  • Journal Title: Inflamm Bowel Dis Volume: 17(2) Pages: 491-502
  • DOI: DOI:10.1002/ibd.21384
  • Peer Reviewed
• [Journal Article] Blockade of Interleukin-6 Signaling SupPresses Experimental Autoimmune Uveoretinitis by the Inhibition of Inflammatory Th17 Responses (2010)
  • Author(s): Hohki S, Ohguro N, Haruta H, Nakai K, Terabe F, Serada S, Fuj imoto M, Nomura S, Kawahata H, Kishimoto T, Naka T
  • Journal Title: Exp Eye Res Volume: 91(2) Pages: 162-70
  • DOI: DOI:10.1016/j. exer.2010.04.009
  • Peer Reviewed
• [Journal Article] Green tea polyphenol epigallocatechin gallate inhibits cell signaling by inducing SOCSI gene expression (2010)
  • Author(s): Ripley BJ, Fujimoto M, Serada S, Ohkawara T, Nishikawa T, Terabe F, Matsukawa Y, Stephanou A, Knight RA, Isenberg DA, Latchman DS, Kishimoto T, Naka T.
  • Journal Title: Int Immunol Volume: 22(5) Pages: 359-66
  • DOI: DOI:10.1093/intimm/dxq015
  • Peer Reviewed
• [Journal Article] iTRAQ-based proteomic identification of leucine rich alpha 2 glycoprotein (LRG) as a novel inflammatory biomarker in autoimmune diseases (2010)
  • Author(s): Serada S, Fujimoto M, Ogata A, Terabe F, Hirano T, Iijima H, Shinzaki S, Nishikawa T, Ohkawara T, wahori K, Ohguro N, Kishimoto T, Naka T
  • Journal Title: Ann Rheum Dis Volume: 69 Pages: 770-774
  • DOI: DOI:10.0036/ard.2009.118919
  • Peer Reviewed
• [Journal Article] SOCS1, a negative regulator of cytokine signals and TLR responses, in human liver diseases. Gastroenterol Res Pract
  • Author(s): Fujimoto M, Naka T
  • Journal Title: Online journal 2010; Article ID 470468
  • DOI: DOI:10.1155/2010/470468
  • Peer Reviewed
• [Presentation] Heterogeneous Nuclear RNP-K Is a Novel Cold-Related Autoantigen in Patients with Raynaud' s Phenomenon (2012)
  • Author(s): Serada S, Fujimoto M, Naka T
  • Organizer: ACR2012第78回米国リウマチ学会議
  • Place of Presentation: 米国(ワシントン)
  • Year and Date: 20121109-14
• [Presentation] Leucine rich alpha 2 glycoprotein (LRG) is a novel biomarker for monitoring disease activity in patients with Ulcerative Colitis (2011)
  • Author(s): Serada S, Fujimoto M, Terabe F, Naka T
  • Organizer: 第40回日本免疫学会総会
  • Place of Presentation: 千葉
  • Year and Date: 2011-11-28
• [Presentation] The effect of IL-6 overproduction in vivo on wound healing. Cytokines in Infectious Diseases (2010)
  • Author(s): Fujimoto M, Kotobuki Y, Ktaba S, Ukita T, Terabe F, Haruta H, Kishimoto T, Naka T
  • Organizer: Autoimmune Disorders and Cancer (Cytokines 2010)
  • Place of Presentation: アメリカ(シカゴ)
  • Year and Date: 2010-10-04
• [Presentation] The effect of IL-6 0verproduction on helper cell differentiation in vivo (2010)
  • Author(s): Fujimoto M, Terabe F, Ukita T, Mei Y, Serada S, Nishikawa T, Ripley B, Kishinloto T, Naka T
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: 神戸
  • Year and Date: 2010-08-25
• [Presentation] 自己免疫疾患の新規活動性マーカーとしての leucine rich alpha 2 glycoprotein Proteomics-based identification of leucine rich alpha 2 glycoprotein (LRG) as anovel biomarker associated with disease activity of inflammatory autoimmune disorders (2010)
  • Author(s): 世良田聡、藤本穣、寺部文隆、西川哲平、仲哲治
  • Organizer: 第8回日本プロテオーム学会
  • Place of Presentation: 千葉
  • Year and Date: 2010-07-26
• [Book] Serum leucine-rich alpha-2 glycoprotein is a disease activity biomarker in ulcerative colitis. 潰瘍性大腸炎の疾患活動性マーカーとしての血清ロイシンリッチアルファ2グリコプロテインINTESTINE (2013)
  • Author(s): 工藤進英, 世良田聡, 藤本穣, 仲哲治, 他
  • Total Pages: 112
  • Publisher: 日本メディカルセンター
• [Book] 先端医療シリーズ43循環器疾患の最新医療 (2012)
  • Author(s): 永井良三, 許俊鋭, 鄭忠和, 澤芳樹, 堀正二, 小川聡田, 林胱一, 佐野俊二, 天野篤, 筒井裕之, 小川久雄, 寺田弘司, 世良田聡, 仲哲治
  • Total Pages: 506
  • Publisher: 先端医療技術研究所
• [Patent(Industrial Property Rights)] 膠原病に伴うレイノー症状を診断する方法及び診断用キット (2012)
  • Inventor(s): 仲哲治、藤本穣、世良田聡
  • Industrial Property Rights Holder: 独立行政法人医薬基盤研究所
  • Industrial Property Number: 特許権、特願2012-141434号
  • Filing Date: 2012-06-22
• [Patent(Industrial Property Rights)] 結核検査用バイオマーカー (2012)
  • Inventor(s): 仲哲治、藤本穣、世良田聡、松本智成
  • Industrial Property Rights Holder: 独立行政法人医薬基盤研究所
  • Industrial Property Number: 特許権、特願2012-84996号
  • Filing Date: 2012-04-03
• [Patent(Industrial Property Rights)] 創傷治癒剤 (2010)
  • Inventor(s): 寿 順久、世良田 聡、仲 哲治
  • Industrial Property Rights Holder: 財団法人ヒューマンサイエンス振興財団
  • Industrial Property Number: 特許権、特願2010-151139号
  • Filing Date: 2010-07-01