2021 Fiscal Year Final Research Report
Elucidation of pathophysiology in neural dysfunction of Down syndrome for the drug discovery
| Project/Area Number |
19H03619
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 52050:Embryonic medicine and pediatrics-related
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| Research Institution | Osaka University |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Keywords | ダウン症候群 / iPS細胞 / ゲノム編集技術 |
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| Outline of Final Research Achievements |
Individuals with Down syndrome (DS) commonly show various neurological phenotypes. Besides the specific effects of dosage-sensitive genes on chromosome 21, recent studies have demonstrated that the gain of a chromosome exerts an adverse impact on cell physiology, regardless of the karyotype. In this study, we investigated cellular stress responses in human trisomy 21 and 13 neurons differentiated from patient-derived induced pluripotent stem cells. Neurons of both trisomies showed increased vulnerability to apoptotic cell death, accompanied by dysregulated protein homeostasis. On the other hand, we established a human isogenic cell line panel based on DS-specific induced pluripotent stem cells, the XIST-mediated transcriptional silencing system in trisomic chromosome 21, and genome/chromosome-editing technologies. Comparative analysis and experimental verification using gene modification reveal dose-dependent proliferation-promoting activity of DYRK1A on DS APCs.
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| Free Research Field |
小児科学
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| Academic Significance and Societal Importance of the Research Achievements |
ダウン症候群は700人に1人と高い発症頻度であり、知的障害をもたらす遺伝性疾患では最多である。さらに50年前にはダウン症者の平均寿命は約3歳であったにもかかわらず、医療の進歩により現在では約60歳であり、この50年間で50年以上伸びた。この急激な変化により、これまで気付かれなかった成人期の認知障害が近年大きな問題として浮かび上がってきているがその研究はまったく進まず治療法もない。本研究課題においてえられる成果は、これまであまり顧みられなかったダウン症候群の臨床を前進させ、患者本人のみならずその両親・介護者の日常生活の向上に大きく役立つと期待される。
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