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Elucidating pathogenesis of degenerative myelopathy caused by species-specific aggregation of canine SOD1

阐明犬 SOD1 物种特异性聚集引起的退行性脊髓病的发病机制

基本信息

批准号：
22KJ1574
负责人：
橋本慶
金额：
$ 1.09万
依托单位：
Nagoya University
依托单位国家：
日本
项目类别：
Grant-in-Aid for JSPS Fellows
财政年份：
2023
资助国家：
日本
起止时间：
2023-03-08 至 2024-03-31
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22KJ1574/
关键词：
変性性脊髄症筋萎縮性側索硬化症 SOD1 タンパク質凝集モデルマウス

项目摘要

イヌの変性性脊髄症 (DM)の病因タンパク質であるSuperoxide dismutase-1 (SOD1)の疾患変異体E40Kは、DM罹患犬の脊髄運動神経細胞内に凝集体を形成する。この凝集体が神経細胞へ毒性を発揮すると考えられ、凝集抑制はDMの治療標的の1つとされる。SOD1はヒトの筋萎縮性側索硬化症 (ALS)の病因タンパク質の1つでもあるが、興味深いことにE40K変異はヒトSOD1には凝集を誘導しないことが報告され、追試により確認した。申請者は、このE40K変異による凝集性の種差がイヌおよびヒトSOD1の117番目のアミノ酸残基に依存していることを突き止めた。タンパク質結晶構造解析などのさらなる詳細な検討により、イヌSOD1におけるこの凝集はタンパク質内部の疎水性コアの脆弱性に起因することを明らかにした。以上の研究成果を原著論文にまとめ、投稿中である。次に、E40K変異体の凝集機序に対応した治療候補薬の効果を検証するためにDMモデルマウスの作製に着手した。ヒトSOD1プロモーターおよびヒトSOD1ゲノムを搭載した既存の発現コンストラクトを利用し、イヌSOD1のエクソンおよびヒトSOD1のイントロンを組み合わせたキメラコンストラクトを作製して培養細胞に導入したところ、イヌSOD1の発現を確認した。

The etiology of sexual chiropractic syndrome (DM) was related to the etiology of sexual spondylosis (DM). The Superoxide dismutase-1 (SOD1) disease was caused by E40K, and DM was caused by the formation of intracellular agglutination in dogs with spinal cord kinesia. Agglutination inhibition of DM, toxicity, cytopathic effect and agglutination inhibition. The etiology of SOD1 muscular dystrophic cord sclerosis (ALS) is called myodermoid sclerosis (ALS). This is the cause of the disease. The cause of the disease is related to the etiology of muscular dystrophy. E40K and E40K were used to determine the difference in agglutination, SOD1, 117A, acid residue dependence, acid residue dependence, agglutinability and agglutination. The reason for the formation of the crystal structure is to understand the cause of fragility, the cause of vulnerability, the cause of SOD1, the cause of vulnerability, the cause of vulnerability. The above "research results" are published in the original and submitted articles. In the second, E40K body agglutination machine, the first step is to treat the disease. The result is that you will start to treat the DM virus in the first place. This is the first time that you can use the existing SOD1 data. You can use the existing SOD1 data. You can use it. You can use it. If you want to use it, you will need to use it. If you want to use it, you will need to know that it is possible to use it. You will need to know that it is possible to make sure that you are aware of it. You will be able to make sure that it is possible to make sure that you are using it. You will not be able to do so. You will need to learn how to do it. You will need to know that it is safe to use it. In this case, you will be able to make sure that you are aware of it. You will be able to make sure that it is possible to do so.