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金澤 智カナザワ サトシ

所属部署医学研究科神経発達症遺伝学分野
職名助教
メールアドレス
ホームページURLhttp://www.med.nagoya-cu.ac.jp/molgene.dir/index.html
生年月日
Last Updated :2020/06/02

研究者基本情報

学歴

  •  - 1983年, 埼玉大学, 理学部

学位

  • 埼玉大学理工学研究科生物環境科学専攻/博士(理学)・博士(学術), 博士

所属学協会

  • 米国呼吸器学会
  • 日本炎症・再生医学会
  • 日本分子生物学会
  • 日本呼吸器学会
  • 日本リウマチ学会

委員歴

  •   2009年 - 2011年, 名古屋アポトーシス研究会, 幹事
  •   2006年 - 2008年, 財団法人 中部化が鵜技術センター, プロジェクト形成研究会 代表幹事

経歴

  • 2002- 名古屋市立大学 大学院医学研究科
  • 1996-2002 カルフォルニア大学サンフランシスコ校
  • 1983-1996 オリエンタル酵母工業株式会社

研究活動情報

研究分野

  • ライフサイエンス, 実験動物学
  • ライフサイエンス, 薬系化学、創薬科学
  • ライフサイエンス, 呼吸器内科学
  • ライフサイエンス, 膠原病、アレルギー内科学

研究キーワード

    間質性肺炎, 関節リウマチ, 免疫

論文

  • 間質性肺炎モデルマウスの構築, 三浦 陽子、金澤 智, 分子呼吸器病, 24, (1) 16 - 19,   2020年03月, 招待有り
  • Osteochondrogenesis derived from synovial fibroblasts in inflammatory arthritis model, Yoko Miura and Satoshi Kanazawa, Inflammation and Regeneration,   2020年, 査読有り, 招待有り
  • Effect of H2 treatment in a mouse model of rheumatoid arthritis-associated interstitial lung Disease, J Cell Mol Med., 23, (10) 7043 - 7053,   2019年10月, 査読有り
  • A subpopulation of synovial fibroblasts leads to osteochondrogenesis in a mouse model of chronic inflammatory rheumatoid arthritis., JBMR Plus, 3, (6) ,   2019年06月, 査読有り
  • Kruppel-like factor 4 regulates matrix metalloproteinase and aggrecanase gene expression in chondrocytes, Junji Fujikawa, Yuto Takeuchi, Satoshi Kanazawa, Ahmed G. Nomir, Akiyoshi Kito, Eman Elkhashab, Amr M. Ghaleb, Vincent W. Yang, Shigehisa Akiyama, Ichijiro Morisaki, Takashi Yamashiro, Satoshi Wakisaka, Makoto Abe, CELL AND TISSUE RESEARCH, 370, (3) 441 - 449,   2017年12月, 査読有り, Kruppel-like factor 4 (KLF4) is a zinc finger transcription factor that plays crucial roles during the development and maintenance of multiple organs. We and others have previously shown that KLF4 is involved in bone modeling and remodeling but roles played by KLF4 during skeletogenesis are still not fully understood. Here, we show that KLF4 is expressed in the epiphyseal growth plate and articular chondrocytes. Most articular chondrocytes expressed KLF4 in embryos but it localized only in a subset of superficial zone cells in postnatal mice. When KLF4 was overexpressed in chondrocytes in vitro, it severely repressed chondrocytic gene expressions. Global gene expression profiling of KLF4-transduced chondrocytes revealed matrix degrading proteinases of the matrix metalloproteinase and disintegrin and metalloproteinase with thrombospondin-1 domain families within the group of upregulated genes. Proteinase induction by KLF4 was alleviated by Trichostatin A treatment suggesting the possible involvement of epigenetic mechanisms on proteinase induction by KLF4. These results indicate the possible involvement of KLF4 in physiological and pathological aspects during cartilage development and maintenance.
  • A novel quinone derived from 5-hydroxyindoleacetic acid reacts with protein: Possible participation of oxidation of serotonin and its metabolite in the development of atherosclerosis, Yoji Kato, Kota Oki, Naoko Suga, Shigeki Ono, Akari Ishisaka, Yoko Miura, Satoshi Kanazawa, Michitaka Naito, Noritoshi Kitamoto, Anthony J. Kettle, FREE RADICAL BIOLOGY AND MEDICINE, 101, 500 - 510,   2016年12月, 査読有り, The modification of 5-hydroxyindoleacetic acid (5HIAA) by myeloperoxidase with a xanthine oxidase system was investigated by chromatographic analyses. Two major products were identified as a dimer and quinone (indoleacetate dione) of 5HIAA. The formation of a quinone moiety was also confirmed by chemical trapping with o-phenylenediamine. In the presence of N-acetyl-cysteine (NAC), a quinone-NAC adduct was formed. When glyceraldehyde 3-phosphate dehydrogenase was exposed to the myeloperoxidase system with 5HIAA, quinone adducts were formed on the protein molecule. A monoclonal antibody was prepared using a quinone-modified protein as an immunogen to immunochemically detect the quinone on a protein. The established antibody recognized the quinone-NAC adduct, quinone-modified poly-L-lysine, and quinone-modified low-density lipoprotein. Quinone-modified proteins in human atherosclerotic lesions were immunohistochemically observed using the established antibody to the quinone and also a monoclonal antibody to tryptamine dione-modified protein, suggesting an occurrence of in vivo oxidation of serotonin and 5HIAA, accompanied by covalent adduction to biomolecules.
  • A diagnostic marker for superficial urothelial bladder carcinoma: lack of nuclear ATBF1 (ZFHX3) by immunohistochemistry suggests malignant progression., Makoto Kawaguchi, Noboru Hara, Vladimir Bilim, Hiroshi Koike, Mituko Suzuki, Tae-Sun Kim, Nan Gao, Yu Dong, Sheng Zhang, Yuji Fujinawa, Osamu Yamamoto, Hiromi Ito, Yoshihiko Tomita, Yuchi Naruse, Akira Sakamaki, Yoko Ishii, Koichi Tsuneyama, Masaaki Inoue, Johbu Itoh, Masanori Yasuda, Nobuo Sakata, Cha-Gyun Jung, Satoshi Kanazawa, Hiroyasu Akatsu, Hiroshi Minato, Takayuki Nojima, Kiyofumi Asai, Yutaka Miura, BMC cancer, 16, (1) 805 - 805,   2016年10月18日, 査読有り, BACKGROUND: Pathological stage and grade have limited ability to predict the outcomes of superficial urothelial bladder carcinoma at initial transurethral resection (TUR). AT-motif binding factor 1 (ATBF1) is a tumor suppressive transcription factor that is normally localized to the nucleus but has been detected in the cytoplasm in several cancers. Here, we examined the diagnostic value of the intracellular localization of ATBF1 as a marker for the identification of high risk urothelial bladder carcinoma. METHODS: Seven anti-ATBF1 antibodies were generated to cover the entire ATBF1 sequence. Four human influenza hemagglutinin-derived amino acid sequence-tagged expression vectors with truncated ATBF1 cDNA were constructed to map the functional domains of nuclear localization signals (NLSs) with the consensus sequence KR[X10-12]K. A total of 117 samples from initial TUR of human bladder carcinomas were analyzed. None of the patients had received chemotherapy or radiotherapy before pathological evaluation. RESULTS: ATBF1 nuclear localization was regulated synergistically by three NLSs on ATBF1. The cytoplasmic fragments of ATBF1 lacked NLSs. Patients were divided into two groups according to positive nuclear staining of ATBF1, and significant differences in overall survival (P = 0.021) and intravesical recurrence-free survival (P = 0.013) were detected between ATBF1+ (n = 110) and ATBF1- (n = 7) cases. Multivariate analysis revealed that ATBF1 staining was an independent prognostic factor for intravesical recurrence-free survival after adjusting for cellular grading and pathological staging (P = 0.008). CONCLUSIONS: Cleavage of ATBF1 leads to the cytoplasmic localization of ATBF1 fragments and downregulates nuclear ATBF1. Alterations in the subcellular localization of ATBF1 due to fragmentation of the protein are related to the malignant character of urothelial carcinoma. Pathological evaluation using anti-ATBF1 antibodies enabled the identification of highly malignant cases that had been overlooked at initial TUR. Nuclear localization of ATBF1 indicates better prognosis of urothelial carcinoma.
  • AT motif binding factor 1 (ATBF1) is highly phosphorylated in embryonic brain and protected from cleavage by calpain-1, Sheng Zhang, Tae-Sun Kim, Yu Dong, Satoshi Kanazawa, Makoto Kawaguchi, Nan Gao, Hiroshi Minato, Tsutomu Takegami, Takayuki Nojima, Kiyofumi Asai, Yutaka Miura, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 427, (3) 537 - 541,   2012年10月, 査読有り, ATBF1 is a transcription factor that regulates genes responsible for repairing tissues and the protection of cells from oxidative stress. Therefore reduction of ATBF1 promotes susceptibility to varieties of human diseases including neurodegenerative diseases and malignant tumors. The instability of the protein was found to be an important background of diseases. Because ATBF1 is composed of a large 404-kDa protein, it can be easily targeted by proteinases. The protein instability should be a serious problem for the function in the cells and practically for our biochemical study of ATBF1. We have found that calpain-1 is a protease responsible for the degeneration of ATBF1. We observed distinct difference between embryo and adult brain derived ATBF1 regarding the sensitivity to calpain-1. The comparative study showed that eight phosphorylated serine residues (Ser1600, Ser2634, Ser2795, Ser2804, Ser2900, Ser3431, Ser3613, Ser3697) in embryonic brain, but only one site (Ser2634) in adult brain. As long as these amino acids were phosphorylated, ATBF1 derived from embryonic mouse brain showed resistance to cleavage: however, treatment with calf intestine alkaline phosphatase sensitized ATBF1 to be digested by calpain-1. An inhibitor (FK506) against calcineurin, which is a serine/threonine specific phosphatase enhanced the resistance of ATBF1 against the digestion by calpain-1. Taken together, these results demonstrate that these phosphorylation sites on ATBF1 function as a defensive shield to calpain-1. (C) 2012 Elsevier Inc. All rights reserved.
  • Development of an ELISA for Measurement of Rat Pulmonary Surfactant Protein D Using Monoclonal Antibodies., Exp. Lung Res., 36, 463 - 468,   2010年, 査読有り
  • Aberrant MHC class II expression in mouse joints leads to arthritis with extraarticular manifestations similar to rheumatoid arthritis, Satoshi Kanazawa, Shusuke Ota, Chiyoko Sekine, Toyohiro Tada, Takanobu Otsuka, Takashi Okamoto, Grete Sonderstrup, B. Matija Peterlin, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 103, (39) 14465 - 14470,   2006年09月, 査読有り, Genetic susceptibility to rheumatoid arthritis (RA) is associated with certain MHC class II molecules. To clarify the role of these determinants in RA, we generated the D1CC transgenic mouse that expressed genes involved in antigen processing and presentation by the MHC class II pathway in joints. The class II transactivator, which was transcribed from the rat collagen type II promoter and enhancer, directed the expression of these genes. In D1CC mice congenic for the H-2(q) (DBA/1) background, small amounts of bovine collagen type II in adjuvant induced reproducibly an inflammatory arthritis resembling IRA. Importantly, these stimuli had no effect in DBA/1 mice. Eighty-nine percent of D1CC mice developed chronic disease with joint swelling, redness, and heat in association with synovial proliferation as well as pannus formation and mononuclear infiltration of synovial membranes. Granulomatous lesions resembling rheumatoid nodules and interstitial pneumonitis also were observed. As in patients with RA, anticyclic citrullinated peptide antibodies were detected during the inflammatory stage. Finally, joints in D1CC mice displayed juxtaarticular demineralization, severe joint space narrowing, and erosions, which led to ankylosis, but without the appearance of osteophytes. Thus, aberrant expression of MIHC class II in joints facilitates the development of severe erosive inflammatory polyarthritis, which is very similar to RA.
  • Establishment of a simple and quantitative immunospot assay for detecting anti-type II collagen antibody using an infrared fluorescence imaging system (IFIS), S Ota, S Kanazawa, M Kobayashi, T Otsuka, T Okamoto, JOURNAL OF IMMUNOLOGICAL METHODS, 299, (1-2) 189 - 198,   2005年04月, 査読有り, Antibodies to type II collagen (col II) have been detected in patients with rheumatoid arthritis and in animal models of collagen induced arthritis. Here, we describe a novel method to detect anti-col II antibodies using an immunospot assay with an infrared fluorescence imaging system. This method showed very high sensitivity and specificity, and was simple, with low background levels. It also showed higher reproducibility and linearity, with a dynamic range of approximately 500-fold, than the conventional immunospot assay with enhanced chemiluminescence detection. Using this method we were able to demonstrate the antibody affinity maturation process in mice immunized with col II. In these immunized mice, although cross-reactive antibodies reacting with other collagen species were detected in earlier stages of immunization, the titers of cross-reactive antibodies rapidly diminished after the antigen boost, concomitantly with the elevation of the anti-col II antibody. The method and its possible applications are discussed. (c) 2005 Elsevier B.V All rights reserved.
  • 53BP2 induces apoptosis through the mitochondrial death pathway, S Kobayashi, S Kajino, N Takahashi, S Kanazawa, K Imai, Y Hibi, H Ohara, M Itoh, T Okamoto, GENES TO CELLS, 10, (3) 253 - 260,   2005年03月, 査読有り, The p53 binding protein 2 (53BP2) has been identified as the interacting protein to p53, Bcl-2, and p65 subunit of nuclear factor kappaB (NF-kappaB). The TP53BP2 gene encodes two splicing variants, 53BP2S and 53BP2L, previously known as apoptosis stimulating protein 2 of p53 (ASPP2). We found that these 53BP2 proteins are located predominantly in the cytoplasm and induce apoptosis as demonstrated by cleavage of poly ADP ribose polymerase (PARP) and annexin V staining. Furthermore, we demonstrate that 53BP2 is located in the mitochondria and induces apoptosis associated with depression of the mitochondrial trans-membrane potential (DeltaPsim) and activation of caspase-9. From these findings we conclude that 53BP2 induces apoptosis through the mitochondrial death pathway.
  • Induction of Notch signaling by tumor necrosis factor in rheumatoid synovial fibroblasts, K Ando, S Kanazawa, T Tetsuka, S Ohta, Jiang, X, T Tada, M Kobayashi, N Matsui, T Okamoto, ONCOGENE, 22, (49) 7796 - 7803,   2003年10月, 査読有り, Rheumatoid arthritis ( RA) is characterized by progressive inflammation associated with abberrant proliferation of synoviocytes. In order to explore the characteristics of rheumatoid synovial fibroblasts (RSF), we performed the comparative gene expression profile analysis between RSF and normal synovial. broblasts (NSF) upon tumor necrosis factor (TNF) stimulation. As an initial screening for the genes preferentially induced by TNF in RSF compared with NSF, we have adopted a cDNA array containing well-defined sets of genes responsible for cell growth, cell fate determination, and cellular invasiveness. Differentially expressed genes of interest were confirmed using real-time RT-PCR. We found that TNF induced the expression of Notch-1, Notch-4, and Jagged-2 in RSF. The expression of these proteins was detected in the RA synovial tissues. The nucleus of RA synoviocytes showed strong staining with anti-Notch-1 and Notch-4 antibody. TNF induced the nuclear translocation of Notch intracellular domain in RSF, indicating the elicitation of the Notch signaling. Notch-1, Notch-4, and Jagged-2 proteins were also detected in the developing synovium of mouse embryo. Thus, RSF may have re-acquired the primordial phenotype, accounting for the hyperproliferation and aggressive invasiveness, exhibiting tumor-like phenotype.
  • c-Myc recruits P-TEFb for transcription, cellular proliferation and apoptosis, S Kanazawa, L Soucek, G Evan, T Okamoto, BM Peterlin, ONCOGENE, 22, (36) 5707 - 5711,   2003年08月, 査読有り, c-Myc promotes cellular proliferation, sensitizes cells to apoptosis and prevents differentiation. It binds cyclin T1 structurally and functionally from the positive transcription elongation factor b (P-TEFb). The cyclin-dependent kinase 9 (Cdk9) in P-TEFb then phosporylates the C-terminal domain of RNA polymerase II, which is required for the transition from initiation to elongation of eukaryotic transcription. Inhibiting P-TEFb blocks the transcription of its target genes as well as cellular proliferation and apoptosis induced by c-Myc.
  • Transcriptional profiles of latent human immunodeficiency virus in infected individuals: Effects of tat on the host and reservoir, Lin, X, D Irwin, S Kanazawa, L Huang, J Romeo, TSB Yen, BM Peterlin, JOURNAL OF VIROLOGY, 77, (15) 8227 - 8236,   2003年08月, 査読有り, The persistence of human immunodeficiency virus (HIV) in optimally treated infected individuals poses a major therapeutic problem. In latently infected cells, one of the observed phenotypes is absent elongation of viral transcription. Thus, the positive elongation factor b (P-TEFb), which is usually recruited by NF-kappaB or Tat, is not present on the HIV long terminal repeat (LTR). Although most attempts to activate these proviruses centered on NF-kappaB, we investigated effects of Tat. To this end, we generated transgenic mice, which secreted a chimera between Tat and the green fluorescent protein from beta cells of the pancreas. This extracellular Tat distributed widely, entered nuclei of resting cells, and specifically transactivated the HIV LTR. No deleterious side effects of Tat were found. Next, we determined that Tat can activate latent proviruses in optimally treated infected individuals. In their cells, T-cell activation or exogenous Tat could induce viral replication equivalently. Thus, P-TEFb could activate the majority of the latent HIV, in this case by Tat.
  • Wnt pathway activation in mesothelioma: Evidence of dishevelled overexpression and transcriptional activity of beta-catenin, K Uematsu, S Kanazawa, L You, B He, ZD Xu, K Li, BM Peterlin, F McCormick, DM Jablons, CANCER RESEARCH, 63, (15) 4547 - 4551,   2003年08月, 査読有り, Malignant pleural mesothelioma is a relatively uncommon and yet incurable tumor. The pathogenesis of mesothelioma remains poorly understood. This study evaluated the role of Wnt signaling in mesothelioma. Western blot analysis was conducted to confirm the expression of Dishevelled (Dvl) and cytosolic beta-catenin in matched autologous tissue samples (tumor and normal pleura), malignant pleural effusions, and in established mesothelioma cell lines LRK1A, REN and H513. Thirteen of 15 mesotheliomas examined showed consistent overexpression of Dvl and increased cytosolic beta-catenin levels as compared with controls. To evaluate T-cell factor (Tcf)-dependent transcriptional activity of beta-catenin, luciferase assays were conducted. Fresh mesothelioma. cells (effusion derived), as well as LRK1A, REN, and H513 cell lines showed a significant fold increase (1.5-2.4-fold, P < 0.01) in Tcf-dependent transcriptional activity of β-catenin. To evaluate the biological significance of Dvl function in mesothelioma, a PDZ domain deletion mutant (&UDelta;PDZ-Dvl) was created and stably transfected into LRK1A, REN, and H513. The effect of &UDelta;PDZ-Dvl on mesothelioma, growth was assayed in vitro (colony formation assay in soft agar) and in vivo (s.c. implantation in athymic mice NCRNU-M). In mesothelioma cells tested, &UDelta;PDZ-Dvl-mediated inhibition of Dvl decreased cytosolic β-catenin levels, diminished Tcf-mediated transcription, and suppressed tumorigenesis of LRK1A and REN in vitro and in vivo. &UDelta;PDZ-Dvl also down-regulated expression of c-myc in REN and COX-2 in H513. Our data suggest that in malignant pleural mesothelioma, Wnt signaling is activated through Dvl overexpression and downstream signaling through β-catenin. Inhibition of this signaling leads to significant antitumor effects. These results demonstrate Dvl overexpression in human cancer and, specifically, that Wnt signaling plays a role in mesothelioma pathogenesis. These data offer possible new avenues for therapeutic intervention.
  • RING finger protein AO7 supports the NF-B-mediated transcription by interacting with the transactivation domain of p65 subunit., Asamitsu K, Tetsuka T, Kanazawa S, Okamoto T, J. Biol. Chem., 278, 26879 - 26887,   2003年, 査読有り
  • Humanized mice as a model for rheumatoid arthritis., Eming R, Visconti K, Hall F, Sekine C, Kobayashi K, Chen Q, Cope A, Kanazawa S, Peterlin M, Rijnders A, Boots A, Meijerink J, Sonderstrup G, Arthritis Res., 4, S133 - S140,   2002年, 査読有り
  • Repression of MHC determinants in HIV infection., Kanazawa S, Matija Peterlin B, Microbes Infect., 3, 467 - 473,   2001年, 査読有り
  • Combinations of dominant-negative class II transactivator, p300 or CDK9 proteins block the expression of MHC II genes., Kanazawa S, Peterlin BM, Int Immunol., 13, 951 - 958,   2001年, 査読有り
  • NF-KappaB binds P-TEFb to stimulate transcriptional elongation by RNA polymerase II., Barboric M, Nissen RM, Kanazawa S, Jabrane-Ferrat N, Peterlin BM, Mol Cell., 8, 327 - 337,   2001年
  • Tat competes with CIITA for the binding to P-TEFb and blocks the expression of MHC class II genes in HIV infection, S Kanazawa, T Okamoto, BM Peterlin, IMMUNITY, 12, (1) 61 - 70,   2000年01月, 査読有り, AIDS and the bare lymphocyte syndrome (BLS) are severe combined immunodeficiencies. BLS results from mutations in genes that regulate the expression of class II major histocompatibility (MHC II) determinants. One of these is the class II transactivator (CIITA). HIV and its transcriptional transactivator (Tat) also block the expression of MHC II genes. By binding to the same surface in the cyclin T1, which together with CDK9 forms the positive transcription elongation factor b (P-TEFb) complex, Tat inhibits CIITA. CIITA can also activate transcription when tethered artificially to RNA. Moreover, a dominant-negative CDK9 protein inhibits the activity of MHC II promoters. Thus, CIITA is a novel cellular coactivator that binds to P-TEFb for the expression of its target genes.
  • The class II transactivator CIITA is a transcriptional integrator, JD Fontes, S Kanazawa, N Nekrep, BM Peterlin, MICROBES AND INFECTION, 1, (11) 863 - 869,   1999年09月, 査読有り
  • Interactions between the class II transactivator and CREB binding protein increase transcription of major histocompatibility complex class II genes, JD Fontes, S Kanazawa, D Jean, BM Peterlin, MOLECULAR AND CELLULAR BIOLOGY, 19, (1) 941 - 947,   1999年01月, 査読有り, Class II major histocompatibility (class II) genes are regulated in a B-cell-specific and gamma interferon-inducible fashion. The master switch for the expression of these genes is the class II transactivator (CIITA). In this report, we demonstrate that one of the functions of CIITA is to recruit the CREB binding protein (CBP) to class II promoters. Not only functional but also specific binding interactions between CIITA and CBP mere demonstrated. Moreover, a dominant negative form of CBP decreased the activity of class II promoters and levels of class II determinants on the surface of cells. Finally, the inhibition of class II gene expression by the glucocorticoid hormone could be attributed to the squelching of CBP by the glucocorticoid receptor. We conclude that CBP, a histone acetyltransferase, plays an important role in the transcription of class II genes.
  • Skin abnormality in aged fyn(-/-) fak(+/-) mice, D Ilic, S Kanazawa, H Nishizumi, S Aizawa, T Kuroki, S Mori, T Yamamoto, CARCINOGENESIS, 18, (8) 1473 - 1476,   1997年08月, 査読有り, Focal adhesion kinase (FAK) is a novel non-receptor protein tyrosine kinase implicated in transducing signals from cell surface receptors, Its association with Fyn, a member of the Src family of tyrosine kinases, has been observed in cell lines, To examine in vivo the interaction between these two proteins, Fyn-deficient mice were bred with fak heterozygous mutants (Fak deficiency is embryonic lethal), A majority of animals with the double mutation (fyn(-/-) fak(+/-)) displayed a transient impairment in thymocyte development at four weeks of age, However, all of them developed skin abnormalities at the age of 8-12 months, The most prominent among abnormalities was a greatly increased number and size of sebaceous glands, Also, the epidermis was thickened and hyperkeratotic, These observations would suggest involvement of Fyn and FAK in keratinocyte differentiation.
  • Impaired development of CD4(+) CD8(+) thymocytes by csk-(knock-in) into fyn locus, S Kanazawa, D Ilic, M Hashiyama, M Okada, T Noumura, S Aizawa, T Suda, ONCOGENE, 13, (1) 199 - 204,   1996年07月, 査読有り, p59(fyn) is one of the Src-family kinases thought to play an important role in signaling through T cell receptor, However, Fyn deficiency has caused no overt defects in vivo on T cell development, nor has it caused any changes in the phosphorylation status of molecules such as ZAP-70 which have been proposed as p59(fyn) substrates, This could be explained as being due to compensation of Fyn deficiency by other Src-family kinases, Here, we have 'knocked-in' the csk gene, a negative regulator of Src-family kinases, into fyn locus to challenge the problem of redundant functions among Src-family kinases, The csk-'knock-in' mice displayed atrophy of the thymic cortex and impaired development of CD4(+) CD8(+) thymocytes, This was concomitant with decrease in tyrosine phosphorylation of ZAP-70 and p120(cbl).
  • p59(fyn)-p125(FAK) cooperation in development of CD4(+)CD8(+) thymocytes, S Kanazawa, D Ilic, M Hashiyama, T Noumura, T Yamamoto, T Suda, S Aizawa, BLOOD, 87, (3) 865 - 870,   1996年02月, 査読有り, p59(fyn) is an Src family nonreceptor tyrosine kinase that has been suggested to play an important role in T-cell development and function, p125(FAK) is a unique nonreceptor tyrosine kinase and has been known to respond to integrin-extracellular matrix interactions. To examine their roles in thymocytes, heterozygous fak mutation was introduced into homozygous Fyn deficiency. The double mutation, but neither Fyn deficiency nor FAK heterozygosity alone, displayed impaired development of CD4(+)CD8(+) thymocytes with atrophy of the thymic cortex, suggesting a unique cooperation between p59(fyn) and p125(FAK) in CD4(+)CD8(+) T-cell development. (C) 1996 by The American Society of Hematology.
  • MESODERMAL DEFECT IN LATE-PHASE OF GASTRULATION BY A TARGETED MUTATION OF FOCAL ADHESION KINASE, FAK, Y FURUTA, D ILIC, S KANAZAWA, N TAKEDA, T YAMAMOTO, S AIZAWA, ONCOGENE, 11, (10) 1989 - 1995,   1995年11月, 査読有り, FAK is a unique non-receptor protein tyrosine kinase that was found in cellular focal adhesions. An increasing number of in vitro observations has suggested that FAK mediates signaling through integrins brought about by interactions with extracellular matrix (ECM). It is highly tyrosine-phosphorylated in v-src-transformed cells and during embryogenesis. To clarify the function of FAK in cell-ECM interactions, embryonic phenotype of its mutant was analysed. FAK-deficient embryos could implant and initiate gastrulation normally, but showed abnormalities in. subsequent development. The abnormalities were characterized as a general deficiency in mesoderm, and the phenotype was quite similar to that caused by fibronectin-deficiency. The results suggest that FAK mediates fibronectin-integrin interactions uniquely at this stage of development, thereby playing an essential role in development of mesodermal cell lineages.
  • INTEGRIN STIMULATION DECREASES TYROSINE PHOSPHORYLATION AND ACTIVITY OF FOCAL ADHESION KINASE IN THYMOCYTES, S KANAZAWA, D ILIC, T NOUMURA, T YAMAMOTO, S AIZAWA, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 215, (2) 438 - 445,   1995年10月, 査読有り, FAK, focal adhesion kinase, is expressed in a variety of cell types and has been suggested to transduce signals brought about by integrin-extracellular matrix (ECM) interactions, Integrin stimulation increases tyrosine phosphorylation and activity of FAK in all the cells examined to date. In contrast, in thymocytes stimulation of VLA-4 (alpha(4) beta(1)) and LFA-1 (alpha(L) beta(2)) resulted in a marked decrease in tyrosine phosphorylation and activity of FAK. (C) 1995 Academic Press, Inc.
  • REDUCED SELL MOTILITY AND ENHANCED FOCAL ADHESION CONTACT FORMATION IN CELLS FROM FAK-DEFICIENT MICE, D ILLC, Y FURUTA, S KANAZAWA, N TAKEDA, K SOBUE, N NAKATSUJI, S NOMURA, J FUJIMOTO, M OKADA, T YAMAMOTO, S AIZAWA, NATURE, 377, (6549) 539 - 544,   1995年10月, 査読有り, THE intracellular protein tyrosine kinase FAK (focal adhesion kinase) was originally identified by its high level of tyrosine phosphorylation in v-src-transformed cells(1-4). FAK Is also highly phosphorylated during early development(5,6). In cultured cells it is localized to focal adhesion contacts and becomes phosphorylated and activated in response to integrin-mediated binding of cells to the extracellular matrix, suggesting an important role in cell adhesion and/or migration. We have generated FAK-deficient mice by gene targeting to examine the role of FAK during development. Mutant embryos displayed a general defect of mesoderm development, and cells from these embryos had reduced mobility in vitro. Surprisingly, the number of focal adhesions was increased in FAK-deficient cells, suggesting that PAK may be involved in the turnover of focal adhesion contacts during cell migration.
  • CHARACTERIZATION OF ERYTHROPOIETIN RECEPTOR ON ERYTHROPOIETIN-UNRESPONSIVE MOUSE ERYTHROLEUKEMIA-CELLS, K TODOKORO, SKH AMANUMA, Y IKAWA, BIOCHIMICA ET BIOPHYSICA ACTA, 943, (2) 326 - 330,   1988年08月, 査読有り
  • Specific binding of erythropoietin to its receptor on responsive mouse erythroleukemia cells., Proc Natl Acad Sci U S A, 84, 4126 - 4130,   1987年, 査読有り

講演・口頭発表等

  • Runx2+, Sox9+ positive synovial cells differentiate into hyperplastic chondrocytes; it results in bony ankylosis, 三浦 陽子, 金澤 智, 第62回日本リウマチ学会,   2018年
  • A novel interstitial pneumonitis mouse model, D1CC+/+ x D1BC+/+ mouse shows chronic inflammation with severe fibrosis in lung., Satoshi Kanazawa, Yoko Miura, Keystone Symposia, The Resolution of Inflammation in Health and Disease,   2018年
  • Nintedanib attenuates histopathology of interstitial pneumonia in a transgenic mouse model of arthritis, Yoko Miura, Satoshi Kanazawa, Hirotsugu Ohkubo, Akio Niimi, ATS conference 2018,   2018年
  • Ectopic expression of B7.1 (CD80) in chondrocytes leads to chronic inflammatory arthritis in mice,, Yoko Miura, Satoshi Kanazawa, 19th Takeda Science Foundataion Symposium on Bioscience (Osaka),   2017年
  • 関節リウマチマウスモデル(D1CCxD1BCマウス)における間質性肺炎誘導, 金澤 智, 第60回日本リウマチ学会総会,   2016年04月

特許

  • 新規抗PAD4抗体, 金澤 智, 特願2017-249589
  • 間質性肺炎モデル動物及びその用途, 金澤 智, 特願2015-49568, 特開2016-6734, 特許第5888693
  • 新規抗PAD4抗体, 金澤 智, 特願2015-044518
  • Transgenic nonhuman mammal representing the pathologic conditions of human rheumatoid arthritis, 米国特許番号US7745690
  • ヒト関節リウマチの病態を再現するトランスジェニック非ヒト哺乳動物, 特許第5099550号
  • ヒト関節リウマチの病態を再現するトランスジェニック非ヒト哺乳動物, 特許第4857450号

受賞

  •   2012年, 第33回日本炎症・再生医学会 優秀演題賞
  •   2011年, 第32回日本炎症・再生医学会 優秀賞
  •   2006年, 名古屋市立大学医学会賞

競争的資金

  • 抗PAD4抗体を用いた治療薬開発, AMED, 橋渡し研究戦略的推進プログラム シーズA(継続),   2019年04月 - 2020年03月
  • 活性阻害型抗PAD4抗体を用いた関節リウマチおよび間質性肺炎抑制メカニズムの検討, 日本学術振興会, 基盤C,   2017年04月 - 2020年03月
  • 抗PAD4抗体を用いた治療薬開発, AMED, 橋渡し研究戦略的推進プログラム シーズA,   2018年04月 - 2019年03月
  • ヒト化抗PAD4抗体を用いた関節リウマチ治療へ向けての基礎検討, 日本学術振興会, 基盤C,   2014年04月 - 2017年03月
  • 自己免疫疾患の早期原因分子に対する抗体医薬 開発, 経済産業書, 戦略的基盤技術高度化支援事業,   2014年04月 - 2015年03月
  • 関節リウマチ早期治療を目的と した抗PAD4抗体医薬の検討, 日本学術振興会, 基盤C,   2011年04月 - 2015年03月
  • 早期リウマチ原因因子をターゲットにした新規関節リウマチ抗体医薬の開発, 科学技術振興機構, 研究成果最適展開支援プログラム(A-STEP)顕在化タイプ,   2012年04月 - 2013年03月
  • 特発性間質性肺炎に対する新規薬剤スクリーニング受託試験の上市を目指した研究, 科学技術振興機構, 研究成果最適展開支援プログラム(A-STEP)探索タイプ,   2012年04月 - 2013年03月
  • 特発性間質性肺炎モデル樹立を目指した既存治療薬による実用試験, 科学技術振興機構, 研究成果最適展開支援プログラム(A-STEP)探索タイプ,   2011年04月 - 2013年03月

教育活動情報

担当経験のある科目

  • 実験手法概論, 名古屋市立大学 医学部
  • 生命倫理入門, 名城大学 人間学部
  • Science Writing and Presentation, 名古屋市立大学 医学部


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