研究活動

当科ではUCDavis（University of California, Davis, School of Medicine）や田附興風会医学研究所北野病院と連携し、主に、自己免疫疾患の治療や診断に関する研究を行っております。

研究目標

自己免疫疾患の治療はステロイドや免疫抑制薬による白血球の機能の制御が中心となっているが、これらの薬剤は、生体防御に必要な炎症反応や白血球機能までも非特異的に抑制するため、重篤な感染症を引き起こすことがある。我々のグループでは、自己免疫疾患の発症に関与している白血球やサイトカインのみを特異的に抑制することができる薬剤の開発を目指している。

研究内容

接着因子インテグリンの新規リガンドを同定し、新たなインテグリンの機能を解明するとともに、リガンド―インテグリン間相互作用を抑制する分子を作成し、インテグリン制御による自己免疫疾患の新たな治療法の開発を行っている。

特徴 1：UCDavis との共同研究

特徴 2：Molecular simulationを駆使したタンパク質間相互作用予測

Recent papers(Selected)
Front Cell Dev Biol. 2024 May 9;12:1347616
Cells. 2023;12(18):2265.
Cells 2022;11(19), 3059
Front Immunol. 2022;13:938173.
J Immunol 2021;207:1-8.
Biochem J. 2018;475:723-732.
Cytokine Growth Factor Rev. 2017:34:67-72.
Protein reviews.2017;925:103-115.
J Biol Chem. 2015;290:259-271.
J Biol Chem. 2013; 288:19593-603.
J Biol Chem 2013;288:3059-3069.
J Immunol. 2012;189:5809-5819.
J Biol Chem. 2012;287:12491-12500.

特許：United States Patent：10,591,471
Suppression of SPLA2-integrin binding for treating an
inflammatory condition or suppressing cell proliferation

Publications:
Takada YK, Yu J, Ye X, Wu CY, Felding BH, Fujita M, Takada Y.
The heparin-binding domain of VEGF165 directly binds to integrin αvβ3 and VEGFR2/KDR D1: a potential mechanism of negative regulation of VEGF165 signaling by αvβ3. Front Cell Dev Biol. 2024 May 9;12:1347616

Kurahashi S, Toda N, Sato R, Fujita K, Takeoka J, Ishii A, Fujita M, Komiya T. Diagnosis of pseudo-acute kidney injury: mesothelial cells in the urine. Kidney Int. 2024 Jun;105(6):1325.

Mochizuki K, Toda N, Fujita M, Kurahashi S, Hirashima H, Yoshioka K, Kitagawa T, Ishii A, Komiya T. A Case of Atypical Hemolytic Uremic Syndrome Triggered by Acute Pancreatitis in a Patient with a Membrane Cofactor Protein (CD46) Genetic Variant.Intern Med. 2024 Feb 26. doi: 10.2169/internalmedicine.3169-23.

Takada Y, Fujita M, Takada YK. Virtual Screening of Protein Data Bank via Docking Simulation Identified the Role of Integrins in Growth Factor Signaling, the Allosteric Activation of Integrins, and P-Selectin as a New Integrin Ligand. Cells. 2023 Sep 13;12(18):2265.

Takada YK, Fujita M, Takada Y. Pro-Inflammatory Chemokines CCL5, CXCL12, and CX3CL1 Bind to and Activate Platelet Integrin αIIbβ3 in an Allosteric Manner Cells 2022, 11(19), 3059; https://doi.org/10.3390/cells11193059 - 29 Sep 2022

Fujita C, Sakurai Y, Yasuda Y, Homma R, Huang CL, Fujita M. mCRP as a Biomarker of Adult-Onset Still's Disease: Quantification of mCRP by ELISA. Front Immunol. 2022 Jul 1;13:938173.

Ogawa M, Toda N, Kurahashi S, Fujita K, Tanigaki K, Hirashima H, Fujita M, Komiya T. Bisalbuminemia in nephrotic syndrome. Kidney Int. 2022 Oct;102(4):943. doi: 10.1016/j.kint.2022.04.039.

Wada S, Hirano H, Uehara N, Kurotobi Y, Tsuzaki K, Takamatsu N, Fujita M, Hamano T. Cervical Root Enlargement in Segmental Zoster Paresis: A Study with Magnetic Resonance Imaging and Nerve Ultrasound. Intern Med. 2022 Aug 1;61(15):2361-2365

Fujita-C, Sakurai-Y, Yasuda-Y, Takada-Y, Huang-CL, Fujita-M. Anti-monomeric C-reactive protein antibody ameliorates arthritis and nephritis in mice. J Immunol 2021;207:1-8.

Takeoka-J, Oka-T, Fujita-K, Kurahashi-S, Toda-N, Komiya-T, Fujita-M.Treatment of Secondary Immune Thrombocytopenia with Tacrolimus Clinical Images and Case Reports Journal　2021;Nov 14

Kurahashi S, Toda N, Fujita M, Tanigaki K, Takeoka J, Hirashima H, Muso E, Io K, Sakurai T, Komiya TAcute Tubulointerstitial Nephritis in Rosai-Dorfman Disease Mimicking IgG4-related Disease.Intern Med. 2021 Sep 18.

Toda N, Takeoka J, Tanigaki K, Hirashima H, Fujita M, Komiya T.Two episodes of acute dyspnea that were induced by COVID-19 in a peritoneal dialysis patient. CEN Case Rep. 2021 Jul 16:1-4.

Nakakubo Y, Yamamoto K, Fujita M Atypical Presenting Symptoms of Acute Onset Acquired Haemophilia with EosinophiliFasciitis. Eur J Case Rep Intern Med. 2020 Jun 15;7(9):001722.

Sumitomo R, Hirai T, Fujita M, Murakami H, Otake Y, Huang CL. M2 tumor-associated macrophages promote tumor progression in non-small-cell lung cancer. Exp Ther Med. 2019 Dec;18(6):4490-4498

Sumitomo R, Hirai T, Fujita M, Murakami H, Otake Y, Huang CL. PD-L1 expression on tumor-infiltrating immune cells is highly associated with M2 TAM and aggressive malignant potential in patients with resected non-small cell lung cancer.　Lung Cancer. 2019 Aug 31;136:136-144

Yagita M, Hata S, Miyata H, Kakita H, Tsukamoto T, Muso E, Fujita M.　Systemic Lupus Erythematosus Associated with Ovarian Cancer.Intern Med. 2019 Mar 1;58(5):731-735.

Fujita, M., P. Davari, Y.K. Takada, and Y. Takada, Stromal cell-derived factor-1 (CXCL12) activates integrins by direct binding to an allosteric ligand-binding site (site 2) of integrins without CXCR4. Biochem J, 2018. 475(4): p. 723-732. 10.1042/BCJ20170867

Nakano Y, Yamamoto M, Komatsu K, Yagita M, Fujita M.　Hypertrophic Pachymeningitis in Sjögren's Syndrome.　Intern Med. 2018 Feb 1;57(3):413-415.

Takada, Y.K., J. Yu, M. Fujita, J. Saegusa, C.Y. Wu, and Y. Takada, Direct binding to integrins and loss of disulfide linkage in interleukin-1beta (IL-1beta) are involved in the agonistic action of IL-1beta. J Biol Chem, 2017. 292(49): p. 20067-20075. 10.1074/jbc.M117.818302

Takada, Y., Y.K. Takada, and M. Fujita, Crosstalk between insulin-like growth factor (IGF) receptor and integrins through direct integrin binding to IGF1. Cytokine Growth Factor Rev, 2017. 34: p. 67-72. 10.1016/j.cytogfr.2017.01.003

Takashima R, Takamatsu K, Shinkawa Y, Yagita M, Fukui M, Fujita M.　Dermatomyositis Associated with Lung Neuroendocrine Carcinoma.　Intern Med. 2017;56(6):719-724.

Fujita M, Nakano Y, Yagita M. Successful treatment of prokinetic-resistant intestinal pseudo-obstruction and pneumatosis cystoides intestinalis in systemic sclerosis with metronidazole. Rheumatol Int. 2017 Jul;37(7):1213-1215.

Takada, Y. and M. Fujita, Secreted Phospholipase A2 Type IIA (sPLA2-IIA) Activates Integrins in an Allosteric Manner. Adv Exp Med Biol, 2017. 925: p. 103-115. 10.1007/5584_2016_95

Fujita M, Tabuchi Y, Yagita M. Successful treatment of refractory giant cell arteritis with etanercept. Rheumatol Int. 2016 Aug;36(8):1177-9.

Yagita M, Tsujimoto K, Yagita M, Fujita M. Atypical Presenting Symptoms of Acute Onset Systemic Lupus Erythematosus with Enteritis and Cystitis. Case Rep Med. 2016;2016:8579812

Tsujimoto K, Yagita M, Taniguchi M, Fujita M. Successful Use of Plasma Exchange in the Treatment of Corticosteroid-Refractory Eosinophilic Granulomatosis with Polyangiitis Associated with Gastrointestinal Manifestations. Case Reports Immunol. 2016;2016:8341751

Shinkawa Y, Yagita M, Fujita M. Myocarditis in Mixed Connective Tissue Disease: A Case Report. J Clin Case Rep 2016, 6: 679

Yagita M, Hamano T, Hatachi S, Fujita M. Peripheral neuropathies during biologic therapies. Mod Rheumatol. 2016;26(2):288-93

Fujita, M., K. Zhu, C.K. Fujita, M. Zhao, K.S. Lam, M.J. Kurth, Y.K. Takada, and Y. Takada, Proinflammatory secreted phospholipase A2 type IIA (sPLA-IIA) induces integrin activation through direct binding to a newly identified binding site (site 2) in integrins alphavbeta3, alpha4beta1, and alpha5beta1. J Biol Chem, 2015. 290(1): 259-71.

Fujita, M., Y.K. Takada, and Y. Takada, The Chemokine Fractalkine Can Activate Integrins without CX3CR1 through Direct Binding to a Ligand-Binding Site Distinct from the Classical RGD-Binding Site. PLoS One, 2014. 9(5): p. e96372.

Fujita, M., Y.K. Takada, Y. Izumiya, and Y. Takada, The Binding of Monomeric C-Reactive Protein (mCRP) to Integrins alphavbeta3 and alpha4beta1 Is Related to Its Pro-Inflammatory Action. PLoS One, 2014. 9(4): p. e93738. 10.1371/journal.pone.0093738

Fujita, M. and Y. Takada, Integrins as Co-receptors of Fractalkine. Austin Journal of Clinical Immunology, 2014. 1(3).

Ye, L., T. Dickerson, H. Kaur, Y.K. Takada, M. Fujita, R. Liu, J.M. Knapp, K.S. Lam, N.E. Schore, M.J. Kurth, and Y. Takada, Identification of inhibitors against interaction between pro-inflammatory sPLA2-IIA protein and integrin alphavbeta3. Bioorg Med Chem Lett, 2013. 23(1): p. 340-5. 10.1016/j.bmcl.2012.10.080

Mori, S., V. Tran, K. Nishikawa, T. Kaneda, Y. Hamada, N. Kawaguchi, M. Fujita, Y.K. Takada, N. Matsuura, M. Zhao, and Y. Takada, A Dominant-Negative FGF1 Mutant (the R50E Mutant) Suppresses Tumorigenesis and Angiogenesis. PLoS One, 2013. 8(2): p. e57927. 10.1371/journal.pone.0057927

Fujita, M., Y.K. Takada, and Y. Takada, Insulin-like Growth Factor (IGF) Signaling Requires alphavbeta3-IGF1-IGF Type 1 Receptor (IGF1R) Ternary Complex Formation in Anchorage Independence, and the Complex Formation Does Not Require IGF1R and Src Activation. J Biol Chem, 2013. 288(5): p. 3059-69. 10.1074/jbc.M112.412536

Fujita, M., K. Ieguchi, D.M. Cedano-Prieto, A. Fong, C. Wilkerson, J.Q. Chen, M. Wu, S.H. Lo, A.T. Cheung, M.D. Wilson, R.D. Cardiff, A.D. Borowsky, Y.K. Takada, and Y. Takada, An Integrin Binding-defective Mutant of Insulin-like Growth Factor-1 (R36E/R37E IGF1) Acts as a Dominant-negative Antagonist of the IGF1 Receptor (IGF1R) and Suppresses Tumorigenesis but Still Binds to IGF1R. J Biol Chem, 2013. 288(27): p. 19593-603. 10.1074/jbc.M113.470872

Fujita, M., Y.K. Takada, and Y. Takada, Integrins alphavbeta3 and alpha4beta1 Act as Coreceptors for Fractalkine, and the Integrin-Binding Defective Mutant of Fractalkine Is an Antagonist of CX3CR1. J Immunol, 2012. 189(12): p. 5809-5819. 10.4049/jimmunol.1200889

Fujita, M., K. Ieguchi, P. Davari, S. Yamaji, Y. Taniguchi, K. Sekiguchi, Y.K. Takada, and Y. Takada, Cross-talk between integrin alpha6beta4 and insulin-like growth factor-1 receptor (IGF1R) through direct alpha6beta4 binding to IGF1 and subsequent alpha6beta4-IGF1-IGF1R ternary complex formation in anchorage-independent conditions. J Biol Chem, 2012. 287(15): p. 12491-500. 10.1074/jbc.M111.304170

Yamaji, S., J. Saegusa, K. Ieguchi, M. Fujita, Y.K. Takada, and Y. Takada, A novel fibroblast growth factor-1 (FGF1) mutant that acts as an FGF antagonist. PLoS One, 2010. 5(4): p. e10273. 10.1371/journal.pone.0010273

Ieguchi, K., M. Fujita, Z. Ma, P. Davari, Y. Taniguchi, K. Sekiguchi, B. Wang, Y.K. Takada, and Y. Takada, Direct binding of the EGF-like domain of neuregulin-1 to integrins ({alpha}v{beta}3 and {alpha}6{beta}4) is involved in neuregulin-1/ErbB signaling. J Biol Chem, 2010. 285(41): p. 31388-98. M110.113878 [pii]
10.1074/jbc.M110.113878

Misaki K, Morinobu A, Saegusa J, Kasagi S, Fujita-M, Miyamoto Y, Matsuki F, Kumagai S. Histone deacetylase inhibition alters dendritic cells to assume a tolerogenic phenotype and ameliorates arthritis in SKG mice. Arthritis Res Ther. 13(3):R77.

Fujita-M, Hatachi-S, Yagita-M, Acute Chlamydiae pneumoniae infection in the pathogenesis of autoimmune diseases Lupus. 2009;18(2):164-8.

Fujita-M, Komatsu-K, Hatachi-S, Yagita-M. Reversible posterior leukoencephalopathy syndrome in a patient with Takayasu arteritis. Mod Rheumatol. 2008;18(6):623-9.

Fujita-M, Hatachi-S, Yagita-M Dermatomyositis associated with thyroid cancer. Rheumatol Int 2008;29(2):203-5

Hata-A, Fujita-M, Morishima-T, Kumakura-A, Hata-D. Acute cerebellar ataxia associated with primary human herpesvirus-6 (HHV-6) infection: a report of two cases. Journal of Paediatrics and Child Health 2008:44:10:607-609

Fujita-M, Hatachi-S, Yagita-M. Immunohistochemically proven cytomegalovirus gastrointestinal diseases in three patients with autoimmune diseases. Clin Rheumatol. 2008;27(8):1057-9

Fujita-M, Sugiura-R, Lu-Y, Xu-L, Xia-Y, Shuntoh-H, Kuno-T. Genetic interaction between calcineurin and type 2 myosin and their involvement in the regulation of cytokinesis and chloride ion homeostasis in fission yeast. Genetics, 2002 Jul; 161: 971-81

Cheng-H, Sugiura-R, Wu-W, Fujita-M, Lu-Y, Sio-SO,Takegawa-K, Shuntoh-H, Kuno-T. Role of the Rab GTP-binding protein Ypt3 in the fission yeast exocytic pathway,and its connection to calcineurin function. Mol-Biol-Cell, 2002 Aug; 13:2963-76

Fujita-M, Tamegai-H, Eguchi-T, Kakinuma-K. Novel substrate specificity of designer 3-isopropylmalate dehydrogenase derived from Thermus thermophiles HB8.Biosci Biotechnol Biochem. 2001 Dec;65(12):2695-700

Fujita-M, Toyooka-Y, Tamegai-H, Eguchi-T, Kakinuma-K. Arg-94 is crucial to the catalysis of 3-isopropylmalate dehydrogenase from Thermus thermophilus HB8. Journal of Molecular Catalysis B: Enzymatic, 2000 April; 9, 21:149-155

著書

1. 細胞内シグナル伝達研究・フローチャートでみる先端バイオ研究の進め方 　　杉浦麗子，藤田昌昭，春藤久人，久野高義。辻本豪三，田中利男共編;17-23 　　2001年4月　羊土社
2. シグナル伝達カスケードと分子シャペロン・分子シャペロンによる細胞機能制御 杉浦麗子，藤田昌昭，春藤久人，久野高義。永田和宏，森正敬，吉田賢右共編;140-147 2001年6月　シュプリンガー・フェアラーク東京