基本情報
- 所属
- 自治医科大学 医学部生化学講座構造生化学部門 教授
- 学位
- 博士(医学)(1994年3月 自治医科大学)
- J-GLOBAL ID
- 201401018168107794
- researchmap会員ID
- B000237522
- 外部リンク
研究キーワード
22研究分野
9経歴
3-
2022年4月 - 現在
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2020年10月 - 2022年3月
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2011年4月 - 2020年9月
論文
59-
European Journal of Immunology 55(4) 2025年4月19日ABSTRACT Recent evidence indicates that the TCA cycle metabolite fumarate plays a specific role in modulating signaling pathways in immune cells. We have previously shown that dimethyl fumarate (DMF) reduces glutathione (GSH) activity and causes the accumulation of cellular reactive oxygen species (ROS), thereby compromising effector immune responses and metabolic activities in activated T‐cells. However, the precise mechanism by which DMF modulates T‐cell signaling pathways remains to be elucidated. This study demonstrates that DMF inhibits T‐cell proliferation, independent of T‐cell receptor (TCR) engagement, and this response is fully reversible by replenishing GSH. Immunoblot analysis showed that DMF had different impacts on TCR downstream signaling by decreasing MYC expression while promoting the phosphorylation of Akt and Erk1/2. Cell cycle analysis demonstrated that exposure to DMF led to negative regulation of cell cycle‐related proteins and induced T‐cells into G0/G1 arrest, which was also rescued by antioxidants. Several genes related to GSH synthesis were upregulated at the same time, suggesting that a potential compensatory response may occur to reduce oxidative burst following DMF treatment. Our results suggest that DMF‐mediated oxidative stress alters a range of cell signaling pathways, including MYC, leading to cell cycle arrest and a defective proliferative response of T‐cells during activation.
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ImmunoHorizons 8(3) 228-241 2024年3月1日Although the role of aerobic glycolysis in activated T cells has been well characterized, whether and how fatty acids (FAs) contribute to donor T cell function in allogeneic hematopoietic stem cell transplantation is unclear. Using xenogeneic graft-versus-host disease (GVHD) models, this study demonstrated that exogenous FAs serve as a crucial source of mitochondrial respiration in donor T cells in humans. By comparing human T cells isolated from wild-type NOD/Shi-scid-IL2rγnull (NOG) mice with those from MHC class I/II-deficient NOG mice, we found that donor T cells increased extracellular FA uptake, the extent of which correlates with their proliferation, and continued to increase FA uptake during effector differentiation. Gene expression analysis showed the upregulation of a wide range of lipid metabolism-related genes, including lipid hydrolysis, mitochondrial FA transport, and FA oxidation. Extracellular flux analysis demonstrated that mitochondrial FA transport was required to fully achieve the mitochondrial maximal respiration rate and spare respiratory capacity, whereas the substantial disruption of glucose supply by either glucose deprivation or mitochondrial pyruvate transport blockade did not impair oxidative phosphorylation. Taken together, FA-driven mitochondrial respiration is a hallmark that differentiates TCR-dependent T cell activation from TCR-independent immune response after hematopoietic stem cell transplant.
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International Journal of Molecular Sciences 24(3) 2113-2113 2023年1月20日 査読有り筆頭著者責任著者Epigenetic regulation via epigenetic factors in collaboration with tissue-specific transcription factors is curtail for establishing functional organ systems during development. Brain development is tightly regulated by epigenetic factors, which are coordinately activated or inactivated during processes, and their dysregulation is linked to brain abnormalities and intellectual disability. However, the precise mechanism of epigenetic regulation in brain development and neurogenesis remains largely unknown. Here, we show that Tip60/KAT5 deletion in neural stem/progenitor cells (NSCs) in mice results in multiple abnormalities of brain development. Tip60-deficient embryonic brain led to microcephaly, and proliferating cells in the developing brain were reduced by Tip60 deficiency. In addition, neural differentiation and neuronal migration were severely affected in Tip60-deficient brains. Following neurogenesis in developing brains, gliogenesis started from the earlier stage of development in Tip60-deficient brains, indicating that Tip60 is involved in switching from neurogenesis to gliogenesis during brain development. It was also confirmed in vitro that poor neurosphere formation, proliferation defects, neural differentiation defects, and accelerated astrocytic differentiation in mutant NSCs are derived from Tip60-deficient embryonic brains. This study uncovers the critical role of Tip60 in brain development and NSC maintenance and function in vivo and in vitro.
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British Journal of Haematology 2022年2月15日 査読有り
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PLOS ONE 16(7) e0255355-e0255355 2021年7月28日 査読有り責任著者Mitochondrial dysfunction is significantly associated with neurological deficits and age-related neurological diseases. While mitochondria are dynamically regulated and properly maintained during neurogenesis, the manner in which mitochondrial activities are controlled and contribute to these processes is not fully understood. Mitochondrial transcription factor A (TFAM) contributes to mitochondrial function by maintaining mitochondrial DNA (mtDNA). To clarify how mitochondrial dysfunction affects neurogenesis, we induced mitochondrial dysfunction specifically in murine neural stem cells (NSCs) by inactivating Tfam. Tfam inactivation in NSCs resulted in mitochondrial dysfunction by reducing respiratory chain activities and causing a severe deficit in neural differentiation and maturation both in vivo and in vitro. Brain tissue from Tfam-deficient mice exhibited neuronal cell death primarily at layer V and microglia were activated prior to cell death. Cultured Tfam-deficient NSCs showed a reduction in reactive oxygen species produced by the mitochondria. Tfam inactivation during neurogenesis resulted in the accumulation of ATF4 and activation of target gene expression. Therefore, we propose that the integrated stress response (ISR) induced by mitochondrial dysfunction in neurogenesis is activated to protect the progression of neurodegenerative diseases.
MISC
33-
AMERICAN JOURNAL OF MEDICAL GENETICS PART A 167(7) 1465-1465 2015年7月
共同研究・競争的資金等の研究課題
7-
日本学術振興会 科学研究費助成事業 2025年4月 - 2028年3月
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日本学術振興会 科学研究費助成事業 基盤研究(C) 2021年4月 - 2024年3月
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日本学術振興会 科学研究費助成事業 基盤研究(C) 2017年4月 - 2021年3月
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日本学術振興会 科学研究費助成事業 基盤研究(C) 2012年4月 - 2016年3月
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日本学術振興会 科学研究費助成事業 基盤研究(B) 1996年 - 1996年
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日本学術振興会 科学研究費助成事業 奨励研究(A) 1996年 - 1996年
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日本学術振興会 科学研究費助成事業 奨励研究(A) 1995年 - 1995年