Elucidation of the function of novel actin-binding factors in neutrophil phagocytosis and extracellular trap formation
| Project/Area Number |
19K07084
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
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| Research Institution | Okayama University |
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Principal Investigator |
ABE TADASHI 岡山大学, 医学部, 技術専門員 (60423282)
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| Co-Investigator(Kenkyū-buntansha) |
竹居 孝二 岡山大学, 医歯薬学域, 教授 (40322226)
山田 浩司 岡山大学, 医歯薬学域, 准教授 (80325092)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | 細胞外トラップ / ダイナミン / アクチン |
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| Outline of Research at the Start |
体内の細菌の侵入を察知した好中球は、細胞膜とアクチン骨格をダイナミックに再構成し、形態を変化させて殺菌行動に備える。次いで貪食するか、細胞外に放出したクロマチン網で細菌を捕らえ殺菌する。我々は、好中球の機能低下を示すダイナミンの疾患変異解析から、好中球のアクチン再構成に必須な機構（ダイナミンクロスブリッジ）を発見した。ダイナミンは、細胞膜とアクチン再構成を協奏的に制御し殺菌に寄与する可能性が高い。本研究は、「細胞外トラップ」と貪食において、ダイナミンにより膜とアクチン再構成がどのように制御されるのかを明らかにし、好中球殺菌機構の全貌にせまる。
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| Outline of Final Research Achievements |
Neutrophils play an essential role in the destruction of bacteria in innate immune system. In the process of killing pathogens, neutrophils drastically change their cell shape with accompanying the rearrangement of actin cytoskeleton. We found that expressing dynamin 2 K562E mutant, one of the pathogenic mutations in Charcot-Marie-Tooth disease in cells leads to aberrant actin clusters and stress fibers. The effect of this mutant on actin fibers was analyzed in vitro. Recombinant dynamin 2 K562E showed lower self-assembly ability and membrane binding ability than that of dynamin 2 wildtype. Although dynamin K562E directly bundled actin filaments, the formed bundles showed much less ability to bind to the lipid membranes as compared to dynamin 2 wildtype. In conclusion, dynamin 2-mediated interactions between actin and membranes are critical for actin bundle formation in neutrophil functions.
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| Academic Significance and Societal Importance of the Research Achievements |
好中球は細胞膜とアクチン骨格をダイナミックに再構成し、形態を変化させて体内に侵入した細菌の殺菌行動に備える。次いで貪食するか、細胞外に放出したクロマチン網で細菌を捕らえ殺菌する。このクロマチン網は、細胞外トラップと呼ばれ、強力な殺菌手段である。最近、細胞外トラップが自己免疫疾患、がん転移、血栓の過形成への関与が報告され、その形成制御が課題である。本研究は、好中球の貪食及び細胞外トラップ形成に関わる細胞膜とアクチン骨格の再構成機構を解析する研究である。得られる知見は、好中球の殺菌機構の解明のみならず、近年明らかになった好中球細胞トラップ由来の数々の炎症の治療戦略に大きく寄与すると考えられる。
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Report
(4 results)
Research Products
(22 results)
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[Journal Article] Internalization of AMPA-type glutamate receptor in the MIN6 pancreatic beta-cell line2020
Author(s)
The Mon La, Yamada, H., Seiriki, S., Li, S.A., Fujise, K., Katsumi, N., Abe, T., Watanabe, M., Takei, K.
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Journal Title
Cell Struct. Func.
Volume: 45
Issue: 2
Pages: 121-130
DOI
NAID
Related Report
Peer Reviewed / Open Access
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[Journal Article] Dynamin 1 is important for microtubule organisation and stabilisation in glomerular podocytes2020
Author(s)
The Mon La , Tachibana, H., Li, S.A., Abe, T., Seiriki, S., Nagaoka, H., Takashima, E., Takeda, T., Ogawa, D., Makino, S., Asanuma, K., Watanabe, M., Tian, X., Ishibe, S., Sakane, A., Sasaki, T., Wada, J., Takei, K., Yamada, H.
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Journal Title
FASEB Journal
Volume: 34
Issue: 12
Pages: 16449-16463
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] ATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegeneration2019
Author(s)
Takuo Hirose, Alfredo Cabrera-Socorro, David Chitayat, Thomas Lemonnier, Olivier Feraud, Carmen Cifuentes-Diaz, Nicolas Gervasi, Cedric Mombereau, Tanay Ghosh, Loredana Stoica, Al Bacha Jeanne d'arc, Hiroshi Yamada et al.
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Journal Title
Journal of Clinical Investigation
Volume: 130
Issue: 5
Pages: 2145-2162
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Initial phospholipid-dependent Irgb6 targeting to Toxoplasma gondii vacuoles mediates host defense.2019
Author(s)
Lee, Y., Yamada, H., Pradipta, A., Ma, J.S., Okamoto, M., Nagaoka, H., Takashima, E., Standley, D.M., Sasai, M., Takei, K., Yamamoto, M.
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Journal Title
Life Science Alliance
Volume: 3
Issue: 1
Pages: 000-000
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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