Intracellular mechanism for membran repair mediated by ADP-ribosylation
| Project/Area Number |
18K06903
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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 48030:Pharmacology-related
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| Research Institution | Doshisha Women's College of Liberal Arts |
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Principal Investigator |
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 細胞膜修復 / ADP-リボシル化修飾 / 細胞膜傷害 / ADP-リボシル化 / ADP-リボシル化反応 / ADP-ribose |
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| Outline of Final Research Achievements |
Plasma membrane breaks occurs during various pathological conditions, which is directly linked to cell death. Hence, the membrane repair mechanism plays an important role in maintaining homeostasis for the living body. ADP-ribosylation is a post-translational modification of proteins in which ADP-ribose units are sequentially transferred from NAD+ to acceptor proteins by poly(ADP-ribose) polymerase (PARP).
In this study, we found that PARP1, a founding member of PARP family, was activated in response to membrane breaks and catalyzed poly(ADP-ribosyl)ation.Suppression of PARP1 expression by shRNAs or pretreatment with PARP inhibitors inhibited membrane repairs as well as poly(ADP-ribosyl)ation in the damaged area. These results indicate that PARP1 contributes to membrane repair.
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| Academic Significance and Societal Importance of the Research Achievements |
今後、本研究をさらに進めることで臨床応用に発展させていきたいと考えている。現在、器質的ダメージや虚血再灌流障害など細胞膜損傷に伴う病態に対する直接的な治療法は無い。たとえば、虚血性心疾患の治療薬として心臓の負荷の軽減や心機能を改善する効果を狙った対症的治療薬が用いられているが、細胞膜損傷を伴う心筋細胞死に対する直接的な治療薬はない。したがって、本研究は、ADP-リボシル化修飾酵素の未解明の部分を明らかにするという学術的意義に加え、細胞膜損傷によって惹起される疾患、たとえば心不全による心筋細胞死などに対する臨床応用に向けた理論的基盤を提供できたと考えている。
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Report
(4 results)
Research Products
(28 results)
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[Presentation] PARP1 inhibitors alleviate injury in ARH3-deficient mice and human cells2019
Author(s)
山和正, 間下雅士, Bu Xiangning, 加藤治郎, 石渡-遠藤広子, Stevens Linda A, 笠松厚志, Wolfe Lynne A, Toro Camilo, Adams David, Markello Thomas, Gahl William A, Moss Joel
Organizer
第92回日本生化学会大会
Related Report
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[Presentation] Patients with a gene encoding a truncated ADP-ribosyl-acceptor hydrolase 3 exhibit a progressive neurodegenerative phenotype2019
Author(s)
Masato Mashimo, Xiangning Bu, Kazumasa Aoyama, Jiro Kato, Hiroko Ishiwata-Endo, Linda A. Stevens, Atsushi Kasamatsu, Lynne A. Wolfe, Camilo Toro, David Adams, Thomas Markello, William A. Gahl, Joel Moss
Organizer
第42回分子生物学会年会
Related Report
Invited
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[Presentation] Masato Mashimo, Xiangning Bu, Kazumasa Aoyama, Jiro Kato, Hiroko Ishiwata-Endo, Linda A. Stevens, Atsushi Kasamatsu, Lynne A. Wolfe, Camilo Toro, David Adams, Thomas Markello, William A. Gahl, Joel Moss2019
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