Basic understanding of pathophysiology by phenotypic analysis of autistic human brain organoids

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H04813
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 51:Brain sciences and related fields
• Research Institution: Kobe University
• Principal Investigator: Takumi Toru 神戸大学, 医学研究科, 教授 (00222092)
• Project Period (FY): 2021-04-05 – 2024-03-31
• Keywords: 自閉症 / ES細胞 / コピー数多型

Outline of Final Research Achievements

Autism is a developmental disorder represented by social disability, and genetic contributions such as genomic mutation due to copy number variation have been suggested to be responsible for its development. We were the first in the world to construct a comprehensive mouse embryonic stem (ES) cell library using next-generation chromosome engineering as an autism cell model (Autism in a dish). In the analysis of 12 mouse ES cell models among them, we found, among others, abnormalities in translational pathways by single-cell RNA-seq analysis. Furthermore, using human ES cell models with 1q21.1 deletions and duplications, we combined 2D nervous system cultures and 3D organoid brain cultures to obtain data for a comprehensive understanding of human pathology through multidimensional analysis from molecular, morphological, and functional aspects.

Free Research Field

脳科学

Academic Significance and Societal Importance of the Research Achievements

自閉症・統合失調症のモデルとしてヒト染色体1q21.1CNVのヒトES細胞モデルの構築に成功した。本モデルでは、形態、生理的な表現系において、ヒト臨床に近い表現系が見られただけでなく、病態メカニズムの基盤を明らかにすることができた。オルガノイドの更なる長期培養により、より生理的条件に近い3次元モデルとしてデータが期待できる。CNVは病気を起こす遺伝的浸透度が高く、病態理解のためのモデルとして適しており、今後の更なる発展が期待される。本成果は、自閉症を含む精神疾患の病態パスウェイやハブ遺伝子などの創薬シーズに繋がるだけでなく、CNVの発現制御機構の解明というゲノム異常の基盤的理解をもたらす。