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2020 Fiscal Year Final Research Report

Reinforcement of colonic epithelial barrier via mAChR

Research Project

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Project/Area Number 18K06946
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 49010:Pathological biochemistry-related
Research InstitutionAsahikawa Medical College

Principal Investigator

Taniguchi Takanobu  旭川医科大学, 医学部, 教授 (60217130)

Co-Investigator(Kenkyū-buntansha) 矢澤 隆志  旭川医科大学, 医学部, 講師 (00334813)
加藤 剛志  旭川医科大学, 医学部, 准教授 (60194833)
宇和田 淳介  旭川医科大学, 医学部, 助教 (70580314)
Project Period (FY) 2018-04-01 – 2021-03-31
KeywordsTNF / MAP kinase / p38 / ADM17 / STIM1 / SOCE
Outline of Final Research Achievements

In intestinal epithelial cells, store-operated calcium entry (SOCE) following muscarinic M3 receptor activation positively regulates p38MAP kinase and activates the protease ADAM17 to cleave/solubilize TNF-α. It was thought that it blocked the pathway and suppressed the spread of inflammation. In the course of this study, we found PNU-120596 as a substance that inhibits p38MAP kinase. Although this substance is widely used as a positive allosteric modulator of α7 nAChR, it binds directly to p38MAP kinase and exerts an inhibitory effect without mediating α7 nAChR.

Free Research Field

病態医化学

Academic Significance and Societal Importance of the Research Achievements

腸上皮バリアが破綻すると外来抗原や微生物が侵入し、マクロファージなどの免疫細胞が遊走浸潤して対抗し、TNF-αをはじめとする炎症促進因子を放出して腸上皮バリア機能をさらに低下させるという悪循環が生じ、このことは炎症性腸疾患の病態との関わりが深い。我々の研究成果はムスカリン受容体刺激がTNF-α converting enzyme(TACE)を活性化してTNF-α受容体(TNFR)の密度を低下させると同時に、その可溶化された断片(sTNFR)がTNF-α自体を中和してTNF-α経路を抑制していることを示し、炎症性腸疾患の新しい治療法の可能性を示したものである。

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Published: 2022-01-27  

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