| 研究課題/領域番号 |
15K15154
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| 研究機関 | 大阪大学 |
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研究代表者 |
Jun Huang 大阪大学, 免疫学フロンティア研究センター, 特任研究員(常勤) (00751207)
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| 研究期間 (年度) |
2015-04-01 – 2018-03-31
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| キーワード | Treg development / Epigenetic regulation / Etiology of autoimmunity |
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| 研究実績の概要 |
Last year, we have found that deletion of geneX led to impaired development of Tregs. However, it remained unclear whether impaired development of Tregs caused by geneX deletion could lead to breakdown of immune homeostasis.
This year we have confirmed that deletion of geneX resulted in a lethal phenotype. We found that some of the mice developed leukemia-like disease, thus the death of mice with geneX deletion is unlikely to be solely explained by autoimmunity because of impaired Treg development. To address whether there is an autoimmune component in the pathogenesis within those mice, we carried out comprehensive pathological, serological analysis as well as characterization of different immune cells. For all the mice we have analyzed, we detected autoimmunity of various degrees. We identified dilated cardiomyopathy(DCM), gastritis, together with high levels of autoreactive antibodies and increased inflammatory effector cells. We thus established a crucial role for geneX in controlling immune homeostasis via contributing to Treg development.
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| 現在までの達成度 (区分) |
現在までの達成度 (区分)
2: おおむね順調に進展している
理由
We have established a critical role of geneX in the development of thymic Treg cells. By deletion of geneX, we observed a significant reduction of Treg precursors and as well as Treg cells. We excluded the possibility that geneX contributes to Treg development via promoting cell proliferation or anti apoptosis effect using in vitro culture system and transgenic mouse model. We also found that the role of Mbd3 is development-restricted for Tregs, as deletion of geneX does not affect their functions nor their stability.
Through a comprehensive characterization, we revealed that impaired Treg development after geneX deletion led to autoimmune disease, demonstrating geneX as a crucial factor contributing to the establishment of immune homeostasis.
In terms of the mechanism by which geneX contributing to Treg development, using bone-marrow chimera mice model, we revealed that geneX contributing to Treg development in a cell-instrinsic manner, which laid the foundation for further mechanistic investigation.
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| 今後の研究の推進方策 |
Having established a crucial role of geneX in Treg development and revealed its physiological significance, we will start to focus on investigation of the molecular mechanism by which geneX regulates the development of thymic Tregs. We will utilize next generation sequencing based approach to profile the transcriptome and epigenome of Tregs as well as other thymocytes at different developmental stages from both KO and WT mice. We will perform comprehensive bioinformatic analysis to identify transcriptomic and epigenomic alterations by which geneX deletion might contribute to affecting Treg development. In addition, we will try to address the significance of these alterations in a definitive manner.
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| 次年度使用額が生じた理由 |
Research schedule was adjusted according to previous results.
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| 次年度使用額の使用計画 |
Incurring amount will be mainly used for the purchase of reagents, kits and antibodies for next generation sequencing(NGS) library preparation.
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