2023 Fiscal Year Final Research Report
Research on the functional assignment of the IKZF transcription factor by structural difference and on the modulation of transcriptional regulation by mutations in the IKZF1 molecule
| Project/Area Number |
21H02879
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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 | Tokyo Medical and Dental University |
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Principal Investigator |
Morio Tomohiro 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (30239628)
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| Co-Investigator(Kenkyū-buntansha) |
尾崎 富美子 東京医科歯科大学, 大学院医歯学総合研究科, プロジェクト助教 (60795277)
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Keywords | 原発性免疫不全症 / リンパ球分化 / 転写調節 / ダイマー / イカロス / アイオロス |
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| Outline of Final Research Achievements |
In this study, we introduced the split GFP and split AirID systems to clarify the functional differences between homo- and hetero-dimers and found that these systems work in adherent cells. We also generated Ikzf3 G159R, N160S, Ikzf1 N159S mice, and etc., and performed detailed phenotyping in bone marrow, and secondary lymphoid tissues. We also examined in detail the differential dysregulation of expression caused by each mutation. We found that Ikzf3 G159R and N160S have independent dysfunctions, and that at least Ikzf3 N160S plays a part in the pathogenesis by inhibiting Ikzf1 function and hematopoietic cell homing. Long-term follow-up of these mice and sampling of cells and nucleic acids over time was done, which will enable us to analyze mutation accumulation and the change in the accessibility of transcription factors. In addition, several novel IKZF3 mutations were identified from international collaborations; and functional analysis of the mutant molecules was performed.
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| Free Research Field |
小児科学、免疫学
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| Academic Significance and Societal Importance of the Research Achievements |
まず今まで明らかでなかった先天性免疫異常症の責任遺伝子、遺伝子変異が明らかになり、疾患の理解に繋がった。国際共同研究からIKZF3以外の分子の異常も判明した。また、IKZFファミリータンパクの異常による易感染性、自己免疫疾患、悪性腫瘍発症の分子機能を知ることは、これらの疾患の一般的な分子病態の解明や、治療法の開発に繋がると期待される。さらに、ホモダイマー、ヘテロダイマーを形成する転写因子の機能的差異が明らかになれば、発生や分化、腫瘍発生等の分子機能がより明確になり、生体内における分子間相互作用や、複雑な転写制御の理解の一助になると予想される。
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