小児期の全身疾患とヒト固有の生後脳発達
キーワード：自閉スペクトラム症、てんかん、脳免疫相関、インタラクトーム、択一的スプライシング、分子シグナル
2011.04.
主要原著論文
| 1. |
Satoshi Akamine, Sayaka Okuzono, Hiroyuki Yamamoto, Daiki Setoyama, Noriaki Sagata, Masahiro Ohgidani, Takahiro A Kato, Tohru Ishitani, Hiroki Kato, Keiji Masuda, Yuki Matsushita, Hiroaki Ono, Yoshito Ishizaki, Masafumi Sanefuji, Hirotomo Saitsu, Naomichi Matsumoto, Dongchon Kang, Shigenobu Kanba, Yusaku Nakabeppu, Yasunari Sakai, Shouichi Ohga, GNAO1 organizes the cytoskeletal remodeling and firing of developing neurons., FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 10.1096/fj.202001113R, 34, 12, 16601-16621, 2020.12, Developmental and epileptic encephalopathy (DEE) represents a group of neurodevelopmental disorders characterized by infantile-onset intractable seizures and unfavorable prognosis of psychomotor development. To date, hundreds of genes have been linked to the onset of DEE. GNAO1 is a DEE-associated gene encoding the alpha-O1 subunit of guanine nucleotide-binding protein (GαO ). Despite the increasing number of reported children with GNAO1 encephalopathy, the molecular mechanisms underlying their neurodevelopmental phenotypes remain elusive. We herein present that co-immunoprecipitation and mass spectrometry analyses identified another DEE-associated protein, SPTAN1, as an interacting partner of GαO . Silencing of endogenous Gnao1 attenuated the neurite outgrowth and calcium-dependent signaling. Inactivation of GNAO1 in human-induced pluripotent stem cells gave rise to anomalous brain organoids that only weakly expressed SPTAN1 and Ankyrin-G. Furthermore, GNAO1-deficient organoids failed to conduct synchronized firing to adjacent neurons. These data indicate that GαO and other DEE-associated proteins organize the cytoskeletal remodeling and functional polarity of neurons in the developing brain.. |
| 2. |
Yasutaka Nakashima, Yasunari Sakai, Yumi Mizuno, Kenji Furuno, Keiichi Hirono, Shinichi Takatsuki, Hiroyuki Suzuki, Yoshihiro Onouchi, Tohru Kobayashi, Kazuhiro Tanabe, Kenji Hamase, Tomofumi Miyamoto, Ryohei Aoyagi, Makoto Arita, Kenichiro Yamamura, Tamami Tanaka, Hisanori Nishio, Hidetoshi Takada, Shouichi Ohga, Toshiro Hara, Lipidomics links oxidized phosphatidylcholines and coronary arteritis in Kawasaki disease., Cardiovascular research, 10.1093/cvr/cvz305, 117, 1, 96-108, 2021.01, AIMS: Coronary arteritis is a life-threatening complication that may arise in the acute stage of Kawasaki disease (KD), the leading cause of systemic vasculitis in childhood. Various microorganisms and molecular pathogens have been reported to cause KD. However, little is known about the key molecules that contribute to the development of coronary arteritis in KD. METHODS AND RESULTS: To identify causative molecules for coronary arteritis in KD, we prospectively recruited 105 patients with KD and 65 disease controls in four different parts of Japan from 2015 to 2018. During this period, we conducted lipidomics analyses of their sera using liquid chromatography-mass spectrometry (LC-MS). The comprehensive LC-MS system detected a total of 27 776 molecules harbouring the unique retention time and m/z values. In the first cohort of 57 KD patients, we found that a fraction of these molecules showed enrichment patterns that varied with the sampling region and season. Among them, 28 molecules were recurrently identified in KD patients but not in controls. The second and third cohorts of 48 more patients with KD revealed that these molecules were correlated with inflammatory markers (leucocyte counts and C-reactive proteins) in the acute stage. Notably, two of these molecules (m/z values: 822.55 and 834.59) were significantly associated with the development of coronary arteritis in the acute stage of KD. Their fragmentation patterns in the tandem MS/MS analysis were consistent with those of oxidized phosphatidylcholines (PCs). Further LC-MS/MS analysis supported the concept that reactive oxygen species caused the non-selective oxidization of PCs in KD patients. In addition, the concentrations of LOX-1 ligand containing apolipoprotein B in the plasma of KD patients were significantly higher than in controls. CONCLUSION: These data suggest that inflammatory signals activated by oxidized phospholipids are involved in the pathogenesis of coronary arteritis in KD. Because the present study recruited only Japanese patients, further examinations are required to determine whether oxidized PCs might be useful biomarkers for the development of coronary arteritis in broad populations of KD.. |
| 3. |
Sayaka Okuzono, Fumihiko Fujii, Yuki Matsushita, Daiki Setoyama, Yohei Shinmyo, Ryoji Taira, Kousuke Yonemoto, Satoshi Akamine, Yoshitomo Motomura, Masafumi Sanefuji, Takeshi Sakurai, Hiroshi Kawasaki, Kihoon Han, Takahiro A Kato, Hiroyuki Torisu, Dongchon Kang, Yusaku Nakabeppu, Yasunari Sakai, Shouichi Ohga, Shank3a/b isoforms regulate the susceptibility to seizures and thalamocortical development in the early postnatal period of mice., Neuroscience research, 10.1016/j.neures.2023.03.001, 2023.03, Epileptic seizures are distinct but frequent comorbidities in children with autism spectrum disorder (ASD). The hyperexcitability of cortical and subcortical neurons appears to be involved in both phenotypes. However, little information is available concerning which genes are involved and how they regulate the excitability of the thalamocortical network. In this study, we investigate whether an ASD-associated gene, SH3 and multiple ankyrin repeat domains 3 (Shank3), plays a unique role in the postnatal development of thalamocortical neurons. We herein report that Shank3a/b, the splicing isoforms of mouse Shank3, were uniquely expressed in the thalamic nuclei, peaking from two to four weeks after birth. Shank3a/b-knockout mice showed lower parvalbumin signals in the thalamic nuclei. Consistently, Shank3a/b-knockout mice were more susceptible to generalized seizures than wild-type mice after kainic acid treatments. Together, these data indicate that NT-Ank domain of Shank3a/b regulates molecular pathways that protect thalamocortical neurons from hyperexcitability during the early postnatal period of mice.. |
所属学会名
日本小児神経学会
日本人類遺伝学会
日本てんかん学会
日本小児科学会
米国人類遺伝学会
北米神経学会
日本分子生物学会
学協会役員等への就任
2016.06～2017.06, 日本小児神経学会, 評議員.
2013.06～2013.06, 福岡・久留米てんかん研究会, 世話人.
2013.06～2013.06, 福岡・久留米てんかん研究会, 世話人.
2013.04～2013.06, 福岡臨床と脳波懇話会, 世話人.
2013.04～2013.06, 日本小児神経学会九州地方会, 世話人.
2013.04～2013.06, 福岡小児神経研究会, 世話人.
学会大会・会議・シンポジウム等における役割
2014.04.01～2016.03.31, 福岡小児神経研究会, 世話人.
2014.04.01～2016.03.31, 日本小児神経学会九州地方会, 世話人.
2014.12.01～2016.03.31, 日本小児科学会福岡地方会, 世話人.
2011.10.08～2011.10.08, 日本小児科学会福岡地方会, 座長（Chairmanship）.
2016.08.07～2016.08.07, 第81回日本小児神経学会九州地方会, 会長.
2016.07.09～2016.07.09, 第11回日本てんかん学会九州地方会, 会長.
学会誌・雑誌・著書の編集への参加状況
2019.05～2023.05, 脳と発達, 国内, 編集委員.
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 |
| 2018年度 |
7 |
7 |
0 |
0 |
14 |
| 2017年度 |
7 |
0 |
0 |
0 |
7 |
| 2016年度 |
5 |
0 |
0 |
0 |
5 |
| 2015年度 |
6 |
0 |
0 |
0 |
6 |
海外渡航状況, 海外での教育研究歴
Howard Hughes Medical Institute, Department of Molecular and Human Genetics, Baylor College of Medicine (The laboratory of Dr. Huda Y Zoghbi), UnitedStatesofAmerica, 2006.04～2011.03.
第19回小児医学川野賞, 川野小児医学奨学財団, 2019.03.
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)
2019年度～2022年度, 基盤研究(C), 代表, 皮質オルガノイドを用いたてんかん性脳症の収束的メカニズムおよび治療研究.
2015年度～2017年度, 基盤研究(C), 代表, Pten変異マウスを用いた新しいてんかん病理・治療モデルの確立.
2012年度～2014年度, 挑戦的萌芽研究, 代表, 精神遅滞関連タンパク質複合体による生後脳発達の制御メカニズムに関する研究.
科学研究費補助金の採択状況(文部科学省、日本学術振興会以外)
2018年度～2019年度, 厚生労働科学研究費補助金 (厚生労働省), 分担, 今回の研究では、川崎病患者105例の血清のリピドミクス解析を行い、川崎病関連28物質を同定した。.
2017年度～2019年度, 厚生労働科学研究費補助金 (厚生労働省), 分担, 小児の脱髄性疾患の実態調査、診断ガイドラインの確立.
2015年度～2016年度, 厚生労働科学研究費補助金 (厚生労働省), 分担, 小児の脱髄性疾患の実態調査、診断ガイドラインの確立.
2002.04～2005.03, 分担, 次世代遺伝子治療の開発.
2017年度, 川野小児医学奨学財団, 研究助成「誘導皮質スフェロイドを用いた早期発症型てんかん性脳症の発症メカニズムと新規治療法の探索」.
2015年度, 公益財団法人 てんかん治療研究振興財団, 研究助成「てんかん性脳症に関与する収束的分子シグナルの解明」.
2013年度, 公益財団法人 母子健康協会, 小児医学研究助成「SHANK3を中心とする自閉症関連分子シグナルの探索」.
2012年度, 武田科学振興財団
, 研究助成「自閉症モデルにおける脳内シグナル伝達異常に関する研究」.
2011年度, ライフサイエンス振興財団, 研究助成金「PTEN遺伝子変異にともなう脳内トランスクリプトーム変化と治療標的の探索」.
