Development of novel frontotemporal lobar degeneration model mice using genome editing.

2018 Fiscal Year Final Research Report

• Project/Area Number: 15K09850
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: HOSOKAWA Masato 公益財団法人東京都医学総合研究所, 認知症・高次脳機能研究分野, 主席研究員 (00435116)
• Research Collaborator: ARAI tetsuaki
• Project Period (FY): 2015-04-01 – 2019-03-31
• Keywords: TDP-43 / C9orf72 / ゲノム編集 / CRISPR-Cas9 / 病態モデル

Outline of Final Research Achievements

Frontotemporal lobar degeneration (FTLD) patients present personality changes and aphasia due to loss of neurons in the frontal and temporal lobes. Among presenile dementias, FTLD is the second most frequent disease. In most FTLD cases, specific proteins form inclusion bodies in neurons and glial cells. TDP-43 and C9orf72 knock-in (KI) mice, which have been clarified in recent years as their main component proteins, were produced by genome editing technology, and the purpose was to develop model mice of FTLD. Although C9orf72-KI mice were not obtained within this research grant period, TDP-43-KI mice were successfully produced. Next, we will investigate whether it is possible to reproduce the same pathology as that of FTLD patient's brain.

Free Research Field

実験病理学

Academic Significance and Societal Importance of the Research Achievements

本研究で作出されたTDP-43-KIマウスは、これまでのTDP-43過剰発現トランスジェニックマウスとは異なり、生理的なTDP-43発現レベルを維持している世界初のマウスである。このマウスを用いてTDP-43蓄積の病理機構を解析することが可能であると考えられる。また、このマウスを用いた前頭側頭葉変性症モデルへ、TDP-43の異常凝集を抑制する候補化合物を投与することにより、疾患に適用できる新たな薬剤開発をおこなうことができると期待される。