2018 Fiscal Year Final Research Report

Interaction between brain function and inflammation mediated by prostaglandin D2

Research Project

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Project/Area Number	16H01881
Research Category	Grant-in-Aid for Scientific Research (A)
Allocation Type	Single-year Grants
Section	一般
Research Field	Biomolecular chemistry
Research Institution	The University of Tokyo (2018) University of Tsukuba (2016-2017)
Principal Investigator	Urade Yoshihiro 東京大学, 医学部附属病院, 特任研究員 (10201360)
Co-Investigator(Kenkyū-buntansha)	藤森功大阪薬科大学, 薬学部, 教授 (70425453) 相原一東京大学, 医学部附属病院, 教授 (80222462) 供田洋北里大学, 薬学部, 教授 (70164043) 島本茂近畿大学, 理工学部, 講師 (00610487)
Project Period (FY)	2016-04-01 – 2019-03-31
Keywords	睡眠 / 炎症 / 肥満 / 筋ジストロフィー / 血管新生 / サプリメント / 癌 / 危険性薬物
Outline of Final Research Achievements	Prostaglandin(PG) D2 is produced by L or H type of synthases, stimulates DP or CRTH2 receptors, and is involved in regulation of sleep and inflammation. By generating antibodies and various types of gene-manipulated mice for each enzyme and receptor, we demonstrated that PGD2 is produced as the sleep substance by L-PGD2 synthase in the arachnoid membrane, induces a release of adenosine as the second somnogen to stimulate A2A receptor-possessing neurons in the nucleus accumbens, a novel sleep center, and induces sleep; DP receptors are induced in endothelial cells in angiogenic microvessels around tumors and acts as a negative regulator of tumor growth; L-PGD2 synthase and CRTH2 receptors are induced by high fat diet in immature adipocytes and involved in obesity and insulin-resistance; and H-PGD2 synthase and CRTH2 receptors are involved in muscular necrosis of Ducchenne's muscular dystrophy. We developped potent inhibitors for human H-PGD2 synthase and started clinical trials.
Free Research Field	生化学
Academic Significance and Societal Importance of the Research Achievements	睡眠物質に関する研究を発展させ、脳内の睡眠調節系を次々に明らかにした。マウス睡眠解析測定系を利用して、オレキシン受容体拮抗作用による新規睡眠薬スボレキサントの情動性脱力発作（カタプレキシー）、及び、大麻成分による痙攣発作を見出し、両薬物の危険性を公表した。亜鉛酵母、清酒酵母、海藻や米糠のポリフェノールなどの睡眠誘発素材を多数見出し、一部は睡眠サプリメントとして商品化された。国際宇宙ステーションの無重力環境で作成した高品質の蛋白質結晶と大型放射光施設での高分解能構造解析により、炎症に関係する酵素の阻害薬開発を進め、治療法の無い難病であるデュシェンヌ型筋ジストロフィーの臨床治験を開始した。