Underlying mechanisms for immune disorders caused by proteasome dysfunctions
Project/Area Number |
21K19384
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Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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Allocation Type | Multi-year Fund |
Review Section |
Medium-sized Section 49:Pathology, infection/immunology, and related fields
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Research Institution | Wakayama Medical University |
Principal Investigator |
Kaisho Tsuneyasu 和歌山県立医科大学, 先端医学研究所, 教授 (60224325)
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Co-Investigator(Kenkyū-buntansha) |
金澤 伸雄 兵庫医科大学, 医学部, 教授 (90343227)
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Project Period (FY) |
2021-07-09 – 2023-03-31
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Project Status |
Completed (Fiscal Year 2022)
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Budget Amount *help |
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2022: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2021: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
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Keywords | プロテアソーム / タンパク質分解 / 自己炎症 / 免疫不全 / 自己炎症性疾患 / 遺伝子改変マウス |
Outline of Research at the Start |
プロテアソームは、不要あるいは不良のタンパク質の分解除去を担うタンパク質複合体であり、そのサブユニットの遺伝子バリアントにより、自己炎症性疾患をきたす。しかし、適切なモデルマウスがないため、その病態についてはほとんどわかっていない。本研究では、プロテアソームサブユニットの新規の遺伝子バリアントを持つマウスの解析を進め、そのマウスで認められたユニークな免疫病態の分子基盤を解明する。
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Outline of Final Research Achievements |
A novel heterozygous missense variant (p.G156D variant) was commonly detected in the gene encoding the proteasome subunit beta1i in two patients showing autoinflammatory manifestations with acquired immune deficiency. This variant was introduced into mice and analyzed. In the heterozygous mutant mice, acquired immunodeficiency was reproduced and, concerning the innate immune cells, monocytes and neutrophils were increased in number. The results led us to propose a new disease category, proteasome-associated autoinflammatory syndrome with immunodeficiency.
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Academic Significance and Societal Importance of the Research Achievements |
プロテアソームサブユニットの新規の遺伝子バリアントが同定され、そのバリアントを持つマウスにおいてヒト病態が再現された。プロテアソームの機能異常は、稀少疾患ばかりでなく、がん、神経変性、老化などcommon diseaseにおいてもみとめられる。本研究で樹立された遺伝子改変マウスの更なる解析により、プロテアソーム機能異常により生じる様々な病態解明が進むことが期待される。
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Report
(3 results)
Research Products
(58 results)
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[Journal Article] XCR1+ DCs are critical for T cell-mediated immunotherapy of chronic viral infections.2023
Author(s)
E. Domenjo Vila, V. Casella, R. Iwabuchi, E. Fossum, M. Pedragosa, Q. Castellvi, P. Cebollada Rica, T. Kaisho, K. Terahara, G. Bocharov, J. Argilaguet, A. Meyerhans.
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Journal Title
Cell Rep
Volume: 42
Issue: 2
Pages: 112123-112123
DOI
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Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Type 1 conventional dendritic cells maintain and guide the differentiation of precursors of exhausted T cells in distinct cellular niches2022
Author(s)
S. Daehling, A. M. Mansilla, K. Knopper, A. Grafen, D. T Utzschneider, M. Ugur, P. G Whitney, A. Bachem, P. Arampatzi, F. Imdahl, T. Kaisho, D. Zehn, F. Klauschen, N. Garbi, A. Kallies, A.-E. Saliba, G. Gasteiger, S. Bedoui, W. Kastenmuller.
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Journal Title
Immunity
Volume: 55
Issue: 4
Pages: 656-670
DOI
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Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Distinct myeloid antigen-presenting cells dictate differential fates of tumor-specific CD8+ T cells in pancreatic cancer.2022
Author(s)
A. L. Burrack, Z. C. Schmiechen, M. T. Patterson, E. A. Miller, E. J. Spartz, M. R. Rollins, J. F. Raynor, J. S. Mitchell, T. Kaisho, B. T. Fife, I. M. Stromnes.
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Journal Title
JCI Insight
Volume: 7
Issue: 7
Pages: 151593-151593
DOI
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Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] The liver contains distinct interconnected networks of CX3CR1+ macrophages, XCR1+ type 1 and CD301a+ type 2 conventional dendritic cells embedded within portal tracts2022
Author(s)
K. English, S. Yang Tan, R. Kwan, L. E Holz, F. Sierro, C. McGuffog, T. Kaisho, W. R Heath, K. Pa MacDonald, G. W McCaughan, D. G Bowen, P. Bertolino.
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Journal Title
Immunol Cell Biol
Volume: 100
Issue: 6
Pages: 394-408
DOI
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Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] A vaccine targeting resistant tumours by dual T cell plus NK cell attack2022
Author(s)
S. Badrinath, MO. Dellacherie, A. Li, S. Zheng, X. Zhang, M. Sobral, JW. Pyrdol, KL. Smith, Y. Lu, S. Haag, H. Ijaz, F. Connor-Stroud, T. Kaisho, G. Dranoff, GC. Yuan, DJ. Mooney, KW. Wucherpfennig.
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Journal Title
Nature
Volume: 606
Issue: 7916
Pages: 992-998
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Depletion of cDC1 cells upon immunotherapy of established tumors precludes efficacy. Cancer Research Depletion of Conventional Type-1 Dendritic Cells in Established Tumors Suppresses Immunotherapy Efficacy2022
Author(s)
A. Teijeira, S. Garasa, C. luri, C. de Andrea, M. Gato, C. Molina, T. Kaisho, A. Cirella, A. Azpilikueta, S. Wculek, J. Egea, I. Olivera, I. Rodriguez, A. Rouzaut, V. Verkhusha, K. Valencia, D. Sancho, P. Berraondo, I. Melero.
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Journal Title
Cancer Research
Volume: 82
Issue: 23
Pages: 4373-4385
DOI
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Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Augmentation of STING‐induced type I interferon production in COPA syndrome2021
Author(s)
Kato Takashi、Yamamoto Masaki、Honda Yoshitaka、Orimo Takashi、Sasaki Izumi、Murakami Kohei、Hemmi Hiroaki、Fukuda‐Ohta Yuri、Isono Kyoichi、Takayama Saki、Nakamura Hidenori、Otsuki Yoshiro、Miyamoto Toshiaki、Takita Junko、Yasumi Takahiro、Nishikomori Ryuta、Matsubayashi Tadashi、Izawa Kazushi、Kaisho Tsuneyasu
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Journal Title
Arthritis & Rheumatology
Volume: in press
Issue: 11
Pages: 2105-2115
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] IFNβ Is a Potent Adjuvant for Cancer Vaccination Strategies.2021
Author(s)
K. M. Audsley, T. Wagner, C. Ta, H. V. Newnes, A. C. Buzzai, S. A. Barnes, B. Wylie, J. Armitage, T. Kaisho, A. Bosco, A. McDonnell, M. Cruickshank, V. S. Fear, B. Foley, J. Waithman
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Journal Title
Frontiers Immunol
Volume: 12
Pages: 735133-735133
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Heterozygous missense variant of the proteasome subunit β-type 9 causes neonatal-onset autoinflammation and immunodeficiency2021
Author(s)
Kanazawa N, Hemmi H, Kinjo N, Ohnishi H, Hamazaki J, M.H, K.A, M.T, H.S, K.N, K.S, H.Y, I.K, N.R, T.M, Y.Y, T.S, O.T, O.T, K.T, S.I, F.Y, W.N, I.Y, K.K, O.S, T.T, N.K, M.S, Y.K, Kaisho T
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Journal Title
Nature Communications
Volume: 12
Issue: 1
Pages: 0-0
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] Hypomorphic mutation of Lig4 gene in mice predisposes to intestinal inflammation driven by Th1 cells.2022
Author(s)
Y. Yamashita, T. Kato, H. Kosako, S. Iwabuchi, K. Tanaka, K. Nakashima, I. Sasaki, S. Hashimoto, K. Ohshima, T. Kaisho, T. Sonoki, S. Tamura.
Organizer
第84回日本血液学会学術集会
Related Report
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[Presentation] Activation of type 1 interferon signaling in dendritic cells and T cells of the mouse model of COPA syndrome.2022
Author(s)
T.Kato, R.Yamasaki, N.W-Nishiyama. I.Sasaki, S.Kaji, K.Murakami, H.Hemmi, Y.Honda, K.Izawa, Y.Otsuki, T.Matsubayashi, R.Nishikomori, T.Kaisho.
Organizer
第29回日本免疫毒性学会学術年会
Related Report
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[Presentation] Immunotherapy of chronic virus infections: exhausted CD8+ T cell subsets are differentially regulated by XCR1+ DC.2022
Author(s)
A.Meyerhans, E.D-Vila, V.Casella, R.Iwabuxhi, E.Fossum, M.Pedragosa, Q.Castellvi, T.Kaisho, K.Terahara, G.Bocharov, J.Argilaguet.
Organizer
The 16th International Symposium on Dendritic Cells 2022
Related Report
Int'l Joint Research
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[Presentation] Unique location in the immunoproteasome complex of a variant causing proteasome-associated autoinflammatory syndrome with immunodeficiency2021
Author(s)
N. Kanazawa, H. Hemmi, N. Kinjo, H. Ohnishi, J. Hamazaki, H. Mishima, A. Kinoshita, T. Mizushima, S. Murata, K. Yoshiura, T. Kaisho
Organizer
第50回日本免疫学会総会
Related Report
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[Presentation] Sublingual dendritic cell (DC) - T cell clusters and distribution of DCs in the oral cavity2021
Author(s)
Y. Kusumoto, T. Kaisho, H. Hemmi, T. Katakai, T. Honda, J. Kikuta, K. Kataoka, T. Moriya, M. Ishii, K. Kabashima, M. Tomura
Organizer
第50回日本免疫学会総会
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[Presentation] Interstitial Lung Disease and abnormal STING activation in COPA V242G heterozygous variant mice2021
Author(s)
T. Kato, T. Orimo, Y. Fukuda-Ohta, N. Wakaki-Nishiyama, C. Nakai, I. Sasaki, K. Murakami, H. Hemmi, Y. Honda, K. Izawa, Y. Otsuki, T. Matsubayashi, R. Nishikomori, T. Kaisho
Organizer
IEIIS2021: 16th Meeting of the International Endotoxin and Innate Immunity Society (26tth Japanese Endotoxin and innate Immunity Society)
Related Report
Int'l Joint Research
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