2023 Fiscal Year Final Research Report
Missing link from chronic Inflammation to dementia onset/exacerbation: New mechanism and drug target in cerebral small vessel disease
| Project/Area Number |
21K19334
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Review Section |
Medium-sized Section 47:Pharmaceutical sciences and related fields
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| Research Institution | Kyoto University |
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Principal Investigator |
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| Project Period (FY) |
2021-07-09 – 2024-03-31
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| Keywords | CNS炎症 / アストロサイト / 炎症性サイトカイン / Oraiチャネル / TRPチャネル / 血管病変 / 脂質メディエーター / ケモカイン |
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| Outline of Final Research Achievements |
Emerging evidence clearly suggests that vascular dysregulation is more important in the pathogenesis of dementia. Since astrocytes can respond to various stimuli in the central nervous system and contribute to the exacerbation/suppression of pathological conditions, we focused mainly on astrocytes among the cell groups that constitute the blood-brain barrier. In this study, we found that Orai2, a member of the store-operated calcium channel (SOCC) family, is involved in the production of PGE2, a known inflammation-related substance, in the response of astrocytes to simultaneous stimulation with TNFα and IL1α, which are known to induce astrocytes to inflammatory phenotypes. In summary, Orai2 is upregulated in TNFα/IL1α stimulated astrocytes and reduces PGE2 production to some extent, thereby modulating CNS inflammation. Our findings may help to understand how astrocytes are associated with inflammatory responses and to identify new targets that modulate astrocytic reactivity.
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| Free Research Field |
病態生理学
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| Academic Significance and Societal Importance of the Research Achievements |
認知症の克服は、超高齢社会における最優先課題とも言える。近年、末梢の慢性炎症や免疫異常が何らかの形で中枢神経系(CNS)へ広がり、さらに過剰なCNS炎症を経て、難治性神経疾患である認知症の発症/増悪に至っていることが示唆されるようになってきたが、その詳細については不明な点が多い。最近、認知症における血管病変が注目されつつあることから、本研究では血液脳関門を構成する細胞群、特にアストロサイトに着目し研究を進めた。その結果、脳内で最も豊富に存在するグリア細胞であるアストロサイトにおける機能分子について、複数見出すことが出来たため、これらを将来的な創薬標的として期待したい。
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