九州大学 研究者情報
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基本情報 研究活動 教育活動
加藤 大樹(かとう ひろき) データ更新日:2024.02.28

助教 /  歯学研究院 歯学部門 口腔常態制御学講座


主な研究テーマ
ミトコンドリアダイナミクスの生理的意義ついての研究
キーワード:ミトコンドリア, 膜動態
2014.05~2030.12.
研究業績
主要原著論文
1. Kentaro Nonaka, Xu Han, Hiroki Kato, Hiroshi Sato, Haruyoshi Yamaza, Yuta Hirofuji, Keiji Masuda, Novel gain-of-function mutation of TRPV4 associated with accelerated chondrogenic differentiation of dental pulp stem cells derived from a patient with metatropic dysplasia, Biochemistry and Biophysics Reports, 10.1016/j.bbrep.2019.100648, 19, 2019.09, [URL], Metatropic dysplasia is a congenital skeletal dysplasia characterized by severe platyspondyly, dumbbell-like deformity of long tubular bones, and progressive kyphoscoliosis with growth. It is caused by mutations in the gene TRPV4, encoding the transient receptor potential vanilloid 4, which acts as a calcium channel. Many heterozygous single base mutations of this gene have been associated with the disorder, showing autosomal dominant inheritance. Although abnormal endochondral ossification has been observed by histological examination of bone in a patient with lethal metatropic dysplasia, the etiology of the disorder remains largely unresolved. As dental pulp stem cells (DPSCs) are mesenchymal stem cells that differentiate into bone lineage cells, DPSCs derived from patients with congenital skeletal dysplasia might be useful as a disease-specific cellular model for etiological investigation. The purpose of this study was to clarify the pathological association between TRPV4 mutation and chondrocyte differentiation by analyzing DPSCs from a patient with non-lethal metatropic dysplasia. We identified a novel heterozygous single base mutation, c.1855C>T in TRPV4. This was predicted to be a missense mutation, p.L619F, in putative transmembrane segment 5. The mutation was repaired by CRISPR/Cas9 system to obtain isogenic control DPSCs for further analysis. The expression of stem cell markers and fibroblast-like morphology were comparable between patient-derived mutant and control DPSCs, although expression of TRPV4 was lower in mutant DPSCs than control DPSCs. Despite the lower TRPV4 expression in mutant DPSCs, the intracellular Ca2+ level was comparable at the basal level between mutant and control DPSCs, while its level was markedly higher following stimulation with 4α-phorbol 12,13-didecanoate (4αPDD), a specific agonist for TRPV4, in mutant DPSCs than in control DPSCs. In the presence of 4αPDD, we observed accelerated early chondrocyte differentiation and upregulated mRNA expression of SRY-box 9 (SOX9) in mutant DPSCs. Our findings suggested that the novel missense mutation c.1855C>T of TRPV4 was a gain-of-function mutation leading to enhanced intracellular Ca2+ level, which was associated with accelerated chondrocyte differentiation and SOX9 upregulation. Our results also suggest that patient-derived DPSCs can be a useful disease-specific cellular model for elucidating the pathological mechanism of metatropic dysplasia..
2. Huong Thi Nguyen Nguyen, Hiroki Kato, Hiroshi Sato, Haruyoshi Yamaza, Yasunari Sakai, Shoichi Ohga, Kazuaki Nonaka, Keiji Masuda, Positive effect of exogenous brain-derived neurotrophic factor on impaired neurite development and mitochondrial function in dopaminergic neurons derived from dental pulp stem cells from children with attention deficit hyperactivity disorder, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2019.04.084, 2019.01, [URL], Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders and is characterized by impaired attention, hyperactivity, and impulsivity. While multiple etiologies are implicated in ADHD, its underlying mechanism(s) remain unclear. Although previous studies have suggested dysregulation of dopaminergic signals, mitochondria, and brain-derived neurotrophic factor (BDNF) in ADHD, few studies have reported these associations directly. Stem cells from human exfoliated deciduous teeth (SHED) can efficiently differentiate into dopaminergic neurons (DNs) and are thus a useful disease-specific cellular model for the study of neurodevelopmental disorders associated with DN dysfunction. This study aimed to elucidate the relationships between DNs, mitochondria, and BDNF in ADHD by analyzing DNs differentiated from SHED obtained from three boys with ADHD and comparing them to those from three typically developing boys. In the absence of exogenous BDNF in the cell culture media, DNs derived from boys with ADHD (ADHD-DNs) exhibited impaired neurite outgrowth and branching, decreased mitochondrial mass in neurites, and abnormal intracellular ATP levels. In addition, BDNF mRNA was significantly decreased in ADHD-DNs. Supplementation with BDNF, however, significantly improved neurite development and mitochondrial function in ADHD-DNs. These results suggest that ADHD-DNs may have impaired neurite development and mitochondrial function associated with insufficient production of BDNF, which may be improved by exogenous BDNF supplementation. Findings such as these, from patient-derived SHED, may contribute to the future development of treatment strategies for aberrant dopaminergic signaling, mitochondrial functioning, and BDNF levels implicated in ADHD pathogenesis..
3. Yu Zhang, Hiroki Kato, Hiroshi Sato, Haruyoshi Yamaza, Yuta Hirofuji, Xu Han, Keiji Masuda, Kazuaki Nonaka, Folic acid-mediated mitochondrial activation for protection against oxidative stress in human dental pulp stem cells derived from deciduous teeth, Biochemical and biophysical research communications, 10.1016/j.bbrc.2018.11.169, 2019.01, [URL].
4. Xu Han, Kentaro Nonaka, Hiroki Kato, Haruyoshi Yamaza, Hiroshi Sato, Takashi Kifune, Yuta Hirofuji, Keiji Masuda, Osteoblastic differentiation improved by bezafibrate-induced mitochondrial biogenesis in deciduous tooth-derived pulp stem cells from a child with Leigh syndrome, Biochemistry and Biophysics Reports, 10.1016/j.bbrep.2018.11.003, 17, 32-37, 2019.03, [URL].
5. Huong Thi Nguyen Nguyen, Hiroki Kato, Keiji Masuda, Haruyoshi Yamaza, Yuta Hirofuji, Hiroshi Sato, Thanh Thi Mai Pham, Fumiko Takayama, Yasunari Sakai, Shoichi Ohga, Tomoaki Taguchi, Kazuaki Nonaka, Impaired neurite development associated with mitochondrial dysfunction in dopaminergic neurons differentiated from exfoliated deciduous tooth-derived pulp stem cells of children with autism spectrum disorder, Biochemistry and Biophysics Reports, 10.1016/j.bbrep.2018.09.004, 16, 24-31, 2018.12, [URL].
6. Thanh Thi Mai Pham, Hiroki Kato, Haruyoshi Yamaza, Keiji Masuda, Yuta Hirofuji, Hiroshi Sato, Huong Thi Nguyen Nguyen, Xu Han, Yu Zhang, Tomoaki Taguchi, Kazuaki Nonaka, Altered development of dopaminergic neurons differentiated from stem cells from human exfoliated deciduous teeth of a patient with Down syndrome, BMC Neurology, 10.1186/s12883-018-1140-2, 18, 1, 2018.08, [URL].
7. Saki Hirofuji, Yuta Hirofuji, Hiroki Kato, Keiji Masuda, Haruyoshi Yamaza, Hiroshi Sato, Fumiko Takayama, Michiko Torio, Yasunari Sakai, Shoichi Ohga, Tomoaki Taguchi, Kazuaki Nonaka, Mitochondrial dysfunction in dopaminergic neurons differentiated from exfoliated deciduous tooth-derived pulp stem cells of a child with Rett syndrome, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2018.03.077, 498, 4, 898-904, 2018.04, [URL].
8. Yumiko I. Matsuishi, Hiroki Kato, Keiji Masuda, Haruyoshi Yamaza, Yuta Hirofuji, Hiroshi Sato, Hiroko Wada, Tamotsu Kiyoshima, Kazuaki Nonaka, Accelerated dentinogenesis by inhibiting the mitochondrial fission factor, dynamin related protein 1, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2017.12.026, 495, 2, 1655-1660, 2018.01, [URL].
9. Hiroki Kato, Xu Han, Haruyoshi Yamaza, Keiji Masuda, Yuta Hirofuji, Hiroshi Sato, Thanh Thi Mai Pham, Tomoaki Taguchi, Kazuaki Nonaka, Direct effects of mitochondrial dysfunction on poor bone health in Leigh syndrome, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2017.09.045, 493, 1, 207-212, 2017.11, [URL].
10. Hiroshi Sato, Hiroki Kato, Haruyoshi Yamaza, Keiji Masuda, Huong Thi Nguyen Nguyen, Thanh Thi Mai Pham, Xu Han, Yuta Hirofuji, Kazuaki Nonaka, Engineering of Systematic Elimination of a Targeted Chromosome in Human Cells, BioMed Research International, 10.1155/2017/6037159, 2017, 2017.01, [URL].
11. Hiroki Kato, Thanh Thi Mai Pham, Haruyoshi Yamaza, Keiji Masuda, Yuta Hirofuji, Xu Han, Hiroshi Sato, Tomoaki Taguchi, Kazuaki Nonaka, Mitochondria regulate the differentiation of stem cells from human exfoliated deciduous teeth, Cell Structure and Function, 10.1247/csf.17012, 42, 2, 105-116, 2017.05, [URL].
主要総説, 論評, 解説, 書評, 報告書等
主要学会発表等
1. Nguyen, H.T.N., Kato, H., Sato, H., Yamaza, H., Masuda, K. , Brain-derived neurotrophic factor improves neurite development and mitochondrial activity of dopaminergic neurons differentiated from exfoliated deciduous tooth-derived pulp stem cells of children with ADHD., Neuroscience 2019, 2019.10.
学会活動
所属学会名
日本ミトコンドリア学会
歯科基礎医学会
日本細胞生物学会
日本小児神経学会
日本小児歯科学会
日本生化学会
学協会役員等への就任
2011.07~2015.07, Asian Pacific Society of Prion Research, 評議員.
学会大会・会議・シンポジウム等における役割
2016.08.28~2016.08.28, 福岡国際母子総合研究シンポジウム 第14回市民公開講座, 事務局運営.
2016.08.28~2018.08.28, THE 27th FUKUOKA INTERNATIONAL SYMPOSIUM ON PEDIATRIC/MATERNAL-CHILD HEALTH RESEARCH, 事務局運営.
学術論文等の審査
年度 外国語雑誌査読論文数 日本語雑誌査読論文数 国際会議録査読論文数 国内会議録査読論文数 合計
2022年度      
2021年度      
2020年度      
2019年度      
2018年度      
2017年度      
2016年度      
その他の研究活動
海外渡航状況, 海外での教育研究歴
Universität Tübingen, Germany, 2008.10~2011.03.
受賞
第61回宇部興産学術振興財団学術奨励賞, 公益財団法人宇部興産学術振興財団, 2021.04.
第61回日本小児神経学会奨励賞, 日本小児神経学会, 2019.05.
研究資金
科学研究費補助金の採択状況(文部科学省、日本学術振興会)
2022年度~2024年度, 基盤研究(C), 代表, 乳歯幹細胞による稀少難病ドラベ症候群の病態解明.
2019年度~2021年度, 基盤研究(C), 代表, 細胞増殖から分化への転換に連関するミトコンドリア活性制御機構の解明.
2019年度~2021年度, 基盤研究(C), 分担, 性染色体数異常における発達障害機序の解析 ~乳歯歯髄幹細胞による橋渡し研究~.
2019年度~2021年度, 基盤研究(C), 分担, 自閉症児由来乳歯歯髄幹細胞を活用した酸化ストレスとミトコンドリアとの関係解明.
2016年度~2018年度, 基盤研究(C), 代表, 酸化ストレスからみた口唇裂口蓋裂発症機序解明と予防法の開発.
2016年度~2018年度, 挑戦的萌芽研究, 分担, 乳歯で染色体異常疾患を克服するトランスレーショナル研究.
2013年度~2014年度, 若手研究(B), 代表, ミトコンドリア凝集が引き起こす神経細胞死メカニズムの解明.
寄附金の受入状況
2023年度, 公益財団法人てんかん治療研究振興財団 , 疾患特異的ヒト乳歯幹細胞によるドラベ症候群の分子病態解明.
2022年度, 武田科学振興財団, 医学系研究助成.
2021年度, 公益財団法人宇部興産学術振興財団, 学術奨励賞.
2015年度, 貝原守一医学振興財団, 研究助成金.
2015年度, 武田科学振興財団, 医学系研究助成.

九大関連コンテンツ

pure2017年10月2日から、「九州大学研究者情報」を補完するデータベースとして、Elsevier社の「Pure」による研究業績の公開を開始しました。