Development of novel therapeutic approaches for glomerulosclerosis using genetically modified mice
Project/Area Number |
17K08442
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Medical pharmacy
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Research Institution | Mie University |
Principal Investigator |
Gabazza Corina 三重大学, 医学系研究科, 特任講師(研究担当) (10750656)
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Co-Investigator(Kenkyū-buntansha) |
Gabazza Esteban 三重大学, 医学系研究科, 教授 (00293770)
安間 太郎 三重大学, 医学系研究科, 助教 (80773887)
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Project Period (FY) |
2017-04-01 – 2020-03-31
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Project Status |
Completed (Fiscal Year 2019)
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Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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Keywords | 組織線維化 / 転写因子 / Akt経路 / Smad2/3 / トロンボモジュリン / TGFβ1 / G-タンパク質共役受容体 / 腎不全 / 腎線維症 / 細胞内伝達機構 / アポトーシス / カスパーゼ3 / 遺伝子改変マウス / 糖尿病 / 糖尿性腎障害 / 成長因子 / 核酸 / 糸球体硬化症 / 核酸医薬 / RNA干渉 / 細菌 |
Outline of Final Research Achievements |
In present investigation, we evaluated the effect of recombinant human thrombomodulin on the kidney fibrosis and renal failure using a transgenic mouse over-expressing the complete DNA sequence of human transforming growth factor (TGF)β1 specifically in the renal glomeruli. The TGFβ1 transgenic mice treated with the recombinant human thrombomodulin showed significant decreased glomerular and tubulointerstitial deposition of extracellular matrix protein including collagen and fibronectin, reduced renal expression of pro-fibrotic and inflammatory cytokines and decreased activation of the complement system. In vitro and in vivo experiments showed that recombinant human thrombomodulin blocked apoptosis and the epithelial-mesenchymal transition-of podocytes by binding to GPR15 and by subsequent activation of the Akt signaling pathway and blockade of Smad proteins. These results suggest the potential of recombinant human thrombomodulin as a therapeutic drug for chronic kidney disease.
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Academic Significance and Societal Importance of the Research Achievements |
糖尿病、高血圧等の慢性疾患による腎症の悪化に伴い、血液透析を余儀なくされる患者数は増加の一途を辿り、年間約1万人以上の患者が新規透析導入患者とされている。これらの慢性疾患から腎不全に移行した血液透析患者の予後は、他疾患に比較して著しく悪く、その予後改善の対策が急務と考えられる。本研究においては、慢性腎臓疾患に対する新たな治療戦略の開発に繋がっている。従って、本研究で得た成果は、世界に先駆けての腎線維症に対する新規抗線維化剤の開発において画期的な基礎的情報を提供するものと考えられる。
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Report
(4 results)
Research Products
(67 results)
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[Journal Article] Factors leading to failure to diagnose pulmonary malignant tumors using endobronchial ultrasound with guide sheath within the target lesion.2019
Author(s)
Nishii Y, Yasuma T, Ito K, Suzuki Y, Watanabe F, Kobayashi T, Nishihama K, D'Alessandro-Gabazza CN, Fujimoto H, Gabazza EC, Asano F, Taguchi O, Hataji O.
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Journal Title
Respir Res.
Volume: 20
Issue: 1
Pages: 207-207
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Protective Role of Matrix Metalloproteinase-2 in Allergic Bronchial Asthma.2019
Author(s)
Takahashi Y, Kobayashi T, D'Alessandro-Gabazza CN, Toda M, Fujiwara K, Okano T, Fujimoto H, Asayama K, Takeshita A, Yasuma T, Nishihama K, Inoue R, Qin L,Takei Y, Taguchi O, Gabazza EC.
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Journal Title
Front Immunol.
Volume: 10
Pages: 1795-1795
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Renal Injury during Long-Term Crizotinib Therapy2018
Author(s)
Yasuma Taro、Kobayashi Tetsu、D’Alessandro-Gabazza Corina、Fujimoto Hajime、Ito Kentaro、Nishii Yoichi、Nishihama Kota、Baffour Tonto Prince、Takeshita Atsuro、Toda Masaaki、Gabazza Esteban、Taguchi Osamu、Yonemura Shigenori、Hataji Osamu
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Journal Title
International Journal of Molecular Sciences
Volume: 19
Issue: 10
Pages: 2902-2902
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Identification of Halophilic Microbes in Lung Fibrotic Tissue by Oligotyping2018
Author(s)
D’Alessandro-Gabazza Corina N.、Méndez-García Celia、Hataji Osamu、Westergaard Sara、Watanabe Fumiaki、Yasuma Taro、Toda Masaaki、Fujimoto Hajime、Nishihama Kota、Fujiwara Kentaro、Taguchi Osamu、Kobayashi Tetsu、Mackie Roderick I.、Cann Isaac、Gabazza Esteban C.
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Journal Title
Frontiers in Microbiology
Volume: 9
Pages: 1892-1892
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Protein S Exacerbates Chronic Liver Injury and Fibrosis2018
Author(s)
Totoki Toshiaki、D' Alessandro-Gabazza Corina N.、Toda Masaaki、Tonto Prince Baffour、Takeshita Atsuro、Yasuma Taro、Nishihama Kota、Iwasa Motoh.、Horiki Noriyuki、Takei Yoshiyuki、Gabazza Esteban C.
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Journal Title
Am J Pathol
Volume: 印刷中
Issue: 5
Pages: 1195-1203
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] The medicinal mushroom Grifola Gargal ameliorates Allergic bronchial asthma2018
Author(s)
Harada, E., D’Alessandro-Gabazza, C. N., Toda, M., Morizono, T., Totoki, T., Yasuma, T., Nishihama, K., Kobayashi, T. Sumiya, Kawagishi, H., and Gabazza. E. C.
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Journal Title
J. Med. Food
Volume: 21
Issue: 2
Pages: 136-145
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] A Retrospective Comparison of the Clinical Efficacy of Gefitinib, Erlotinib and Afatinib in Japanese Patients with Non-small Cell Lung Cancer2018
Author(s)
Fujiwara A, Yoshida M, Fujimoto H, Nakahara H, Ito K, Nishihama K, Yasuma T, Hataji O, Taguchi O, D'Alessandro-Gabazza CN, Gabazza EC, Kobayashi T
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Journal Title
Oncol Res
Volume: 印刷中
Issue: 7
Pages: 1031-1036
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Smart watch-based coaching with tiotropium and olodaterol ameliorates physical activity in patients with chronic obstructive pulmonary disease2017
Author(s)
Hataji O, Nishii Y, Ito K, Sakaguchi T, Saiki H, Suzuki Y, D'Alessandro-Gabazza C, Fujimoto H, Kobayashi T, Gabazza EC, Taguchi O
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Journal Title
Exp Ther Med
Volume: 14
Pages: 4061-4064
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Oligonucleotide-targeting periostin ameliorates pulmonary fibrosis2017
Author(s)
Tomaru A、Kobayashi T、Hinneh J A、Baffour Tonto P、D'Alessandro-Gabazza C N、Fujimoto H、Fujiwara K、Takahashi Y、Ohnishi M、Yasuma T、Nishihama K、Yoshino M、Takao K、Toda M、Totoki T、Takei Y、Yoshikawa K、Taguchi O、Gabazza E C
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Journal Title
Gene Ther
Volume: 24
Issue: 11
Pages: 706-716
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Low dose of alcohol attenuates pro-atherosclerotic activity of thrombin2017
Author(s)
Toda M, Totoki T, Nakamura C, Yasuma T, D' Alessandro-Gabazza CN, Mifuji-Moroka R, Nishihama K, Iwasa M, Horiki N, Gabazza EC, Takei Y
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Journal Title
Atherosclerosis
Volume: 265
Pages: 215-224
Related Report
Peer Reviewed / Open Access
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[Journal Article] β2 adrenergic agonist suppresses eosinophil-induced epithelial-to-mesenchymal transition of bronchial epithelial cells2017
Author(s)
Kainuma K, Kobayashi T, D'Alessandro-Gabazza CN, Toda M, Yasuma T, Nishihama K, Fujimoto H, Kuwabara Y, Hosoki K, Nagao M, Fujisawa T, Gabazza EC
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Journal Title
Respir Res
Volume: 18
Issue: 1
Pages: 79-79
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] Lung tissue immune cells in TGFβ1 transgenic mouse with lung fibrosis2019
Author(s)
Tomohito Okano,Tetsu Kobayashi,Haruko Saiki,Takumi Fujiwara,Kentaro Asayama,Atsushi Tomaru,Yoshinori Takahashi,Kentaro Fujiwara,Hiroki Nakahara,Hajime Fujimoto,Corina N.D’Alessandro-Gabazza,Esteban C.Gabazza
Organizer
第59回日本呼吸器学会学術講演会
Related Report
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[Presentation] The role of thrombin-activatable fibrinolysis inhibitor in liver fibrosis2019
Author(s)
Toshiaki Totoki, Masaaki Toda, Taro Yasuma, Atsuro Takeshita, Kentaro Fujiwara,Tomohito Okano, Yuko Okano, Kentaro Asayama, Ryo Inoue, Corina N. D’Alessandro-Gabazza, Esteban C.Gabazza
Organizer
第48回日本免疫学会学術集会
Related Report
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[Presentation] Protective effect of protein S in allergic bronchial asthma2019
Author(s)
Taro Yasuma, Atsuro Takeshita, Yuko Okano, Kentaro Asayama, Kentaro Fujiwara,Tomohito Okano, Yoshinori Takahashi, Hajime Fujimoto,Corina N. D’Alessandro-Gabazza, Masaaki Toda, Tetsu Kobayashi, Esteban C.Gabazza
Organizer
第48回日本免疫学会学術集会
Related Report
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[Presentation] Creating a prediction formula for resting energy consumption of patients with COPD and ILD2018
Author(s)
Keisuke Morikawa, Yasunori Imaoka, Hiroyuki Takemura, Kana Kitayama, Shunta Shimoda, Shogo Inaba, Haruka Kusuki, Yu Hashitsume, Momoko Hirose, Yuta Suzuki, Makoto Okada, Corina N. D’Alessandro-Gabazza, Esteban Gabazza, Osamu Taguchi, Osamu Hataji
Organizer
ERS 2018 International Congress
Related Report
Int'l Joint Research
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[Presentation] Coagulation markers in COPD2018
Author(s)
Gunnar Reksten Husebo, Esteban Gabazza, Corina D'Alessandro, Marianne Aanerud, Masaaki Toda, Rune Gronseth, Per S. Bakke, Tomas Mikal Lind Eagan
Organizer
ERS 2018 International Congress
Related Report
Int'l Joint Research
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[Presentation] Thrombin-activable Fibrinolysis Inhibitor (Procarboxypeptidase B2) Deficiency Protects from Carbon Tetrachloride-induced Liver Fibrosis2017
Author(s)
T. Totoki, C.N. D’Alessandro-Gabazza, R. Mifuji-Moroka, K. Nishihama, A. Takeshita, T. Yasuma, Y. Takahashi, K. Fujiwara, M. Toda, M. Nakamura, N. Horiki, M. Iwasa, T. Kobayashi, Y. Takei, E.C. Gabazza
Organizer
ISTH Congress and 63rd Annual SSC Meeting
Related Report
Int'l Joint Research
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[Presentation] Overexpression of Protein S Exacerbates Carbon Tetrachloride-induced Liver Injury and Fibrosis in Mice2017
Author(s)
Totoki Toshiaki, D’Alessandro-Gabazza Corina N., Moroka-Mifuji Rumi, Nishihama Kota, Takeshita Atsuro, Yasuma Taro, Takahashi Yoshinori, Fujiwara Kentaro, Toda Masaaki, Iwasa Motoh, Kobayashi Tetsu, Takei Yoshiyuki, and Gabazza-Esteban
Organizer
BIT’s 2nd Annual World Congress of Digestive Disease-2017
Related Report
Int'l Joint Research
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