Effects of lipid metabolites on pathogenesis of Parkinson's disease

脂质代谢产物对帕金森病发病机制的影响

• 批准号: 18K15439
• 负责人: 任 乾
• 金额: $ 2.66万
• 依托单位: Chiba University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Early-Career Scientists
• 财政年份: 2018
• 资助国家: 日本
• 起止时间: 2018-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-18K15439/
• 关键词: Parkinson's disease; sEH; MPTP

パーキンソン病では、代表的な神経変性疾患である。しかしながら、臨床では根本的な治療薬がないのが現状である。本研究では、エポキシ脂肪酸及びその代謝物酵素sEHに着目し、パーキンソン病の病態におけるsEHの役割を明らかにした、さらにsEHの阻害剤が新規治療ターゲットとしての可能性を示唆された。まず、パーキンソン病のモデル動物であるMPTPを投与したマウスを用い、生理食塩水或いはMPTPを２時間間隔で３回投与した後にsEHの阻害薬TPPUを１日２回、１週間を連続投与する。その後、脳を取り出し、免疫組織化学やWestern blotなどの方法を用い、TPPUがMPTP投与による線条体におけるチロシンハイドロキシラーゼ、ドパミントランスポーター、酸化的ストレスマーカーやミクログリアなどの異常を有意に改善することが確認した。また、sEH遺伝子欠損マウスを用い、生理食塩水或いはMPTPを投与し、同様の実験を行い、MPTP投与によるドパミン神経系の障害が、sEH遺伝子欠損マウスでは有意に抑制されたことが分かった。さらに、sEH遺伝子ベクター（アデノ随伴ウイルスベクター）を投与したマウスを用い、線条体におけるsEHの過剰発現が、MPTPに対する感受性を増加させ、パーキンソン病の発症脆弱性に関わっていることが分かった。また、パーキンソン病患者の死後脳を用い、線条体におけるsEHやαシヌクレインなどのタンパク質の発現を調べ、パーキンソン病患者の線条体におけるsEH とαシヌクレインのタンパク質発現量の増加では相関があることが分かった。さらに、パーキンソン病患者由来のiPS細胞から分化誘導したドパミン神経を用い、sEHのmRNAなどを調べた結果は、患者由来のドパミン神経におけるsEHの発現量は健常者より有意に増加し、TPPUが患者由来のドバミン神経のapoptosisを抑制することが分かった。

She is the representative of the god who has a sexual disorder. There is a fundamental cure for the disease, such as the bed and the bed. In this study, fatty acids and enzymes sEH were used to treat diseases, diseases The MPTP was injected back at intervals of 3 times after treatment, and then the sEH was used to prevent the TPPU from returning to 2 cycles per day and 1 day after the treatment. After treatment, the method of immuno-histochemistry Western blot assay was used, and TPPU MPTP was injected into the body of the body to make sure that there was no significant difference between the two groups. For example, if you don't know how to use it, if you don't want to use it, if you don't have enough water to use it, if you don't have enough water to use it, if you don't want to use it, you can get rid of it. If you don't know what to do, you can't use it. If you don't know what to do, you can't get rid of it. If you don't know what to do, you can't get rid of it. If you don't know what to do, you can't get rid of it. If you don't want to use it, you can get rid of it. If you don't have sEH, you can't get rid of it. If you don't know what to do, you can't get rid of it. If you don't have You need to know how to use it, sEH, MPTP, susceptibility, vulnerability, sensitivity, vulnerability, sensitivity, vulnerability, vulnerability, sensitivity, sensitivity, vulnerability, vulnerability, sensitivity, vulnerability, sensitivity, sensitivity, vulnerability, vulnerability, sensitivity, vulnerability, sensitivity, sensitivity, vulnerability, sensitivity, vulnerability, sensitivity, sensitivity, After the death of the patient, the doctor said that the patient would use it after death, that the body would be used after death, that the body would be used after death, that the sEH would be used, that the disease would be detected, that the patient would be sick, that the patient would have to use the drug after death, and that the dose should be added to the quantity of the patient after death. The cause of the disease is the differentiation of iPS cells. The results show that the patients are suffering from the disease, and that the patients with normal levels of sEH are intentionally affected, and that the patients with TPPU are affected by the inhibition of apoptosis.

项目成果

A key role of soluble epoxide hydrolase in the pathogenesis of Parkinson's disease

可溶性环氧化物水解酶在帕金森病发病机制中的关键作用

• 发表时间: 2018
• 作者: Ren Qian;Ma Min;Yang Jun;Nonaka Risa;Yamaguchi Akihiro;Ishikawa Kei-ichi;Kobayashi Kenta;Murayama Shigeo;Hwang Sung Hee;Saiki Shinji;Akamatsu Wado;Hattori Nobutaka;Hammock Bruce D.;Hashimoto Kenji;Qian Ren
• 通讯作者: Qian Ren

University of California, Davis(米国)

加州大学戴维斯分校（美国）