病態特異的タンパク質間相互作用を標的としたグリーンファルマ研究
キーワード：難治性疾患、筋萎縮、タンパク質間相互作用、創薬育薬
2015.09.

心循環恒常性維持における受容体作動性TRPCチャネルの役割解析
キーワード：心循環恒常性、TRPCチャネル、自律神経系
2018.04.

超硫黄分子の生理的役割解析
キーワード：超硫黄分子、筋肉、ミトコンドリア、再生・修復
2019.04.

コロナウイルスのスパイク（S）タンパク質を標的としたワクチンや治療薬の開発
2022.02～2023.06, 代表者：日下部宜宏, 九州大学大学院農学研究院.

AMED　iPS由来心筋細胞の毒性評価系確立に向けた培養最適化技術の構築
2019.04, 代表者：諫田泰成, 国立医薬品食品衛生研究所, 日本
ヒトiPS由来心筋分化細胞を用いて薬物の不整脈誘発作用や心筋毒性を評価する系を確立するための最適培養条件を決定することを目的とする。.

TRPCチャネル創薬研究
2019.04～2020.03, 代表者：永田龍, 大阪大学, 日本
TRPCチャネルを標的とする新規化合物（特許出願済み）を用いた前臨床試験を実施し、動物レベルでのPOCを確立させる。これにより、企業への導出を目指す。.

新学術領域（文部科学省）　酸素生物学
2014.10～2019.03, 代表者：森泰生, 京都大学, 日本
我々の身体が積極的に低酸素環境を作り出すことで、その恒常性を維持する機構を見出すことを目的とする。.

AMED BINDS事業
2017.04～2022.03, 代表者：大戸茂弘, 九州大学, 日本
九大独自のアカデミア創薬（グリーンファルマ研究）を推進し、企業がやらない・できない革新的医薬品の開発を目指す。.

JST-CREST
2020.04, 代表者：西田基宏, 九州大学, 日本
超硫黄分子の定量イメージング技術開発とその生理的役割の解析.

内分泌誘導型Ca2+チャネルを標的とした新規創薬展開
2011.04～2016.03, 代表者：西田基宏, 九州大学大学院薬学研究院, 日本
心血管リモデリングにおける内分泌誘導型Ca2+チャネル群の役割を明らかにし、新規心不全治療薬の開発に結びつける．.

心血管組織リモデリングにおけるシルニジピンの評価
2011.04～2012.03, 代表者：西田基宏, 九州大学大学院薬学研究院, 日本
心血管リモデリングにおけるL/N型Ca2+チャネル拮抗薬シルニジピンの保護作用およびそのメカニズムを明らかにする．.

システイン修飾による活性酸素受容体機能制御機構の解析
2008.04～2012.03, 代表者：西田基宏, 九州大学大学院薬学研究院, 日本
シグナルタンパク分子に含まれるシステイン残基の翻訳後修飾によって惹起される受容体発現変化とその生理機能との関連を明らかにする。.

心不全におけるG蛋白質の役割解析と新たな創薬標的の探索
2007.04～2010.03, 代表者：西田基宏, 九州大学大学院薬学研究院, 日本
心臓リモデリングに関わるG蛋白質シグナル経路の解析および心不全治療につながる新たな創薬シーズを探索する。.

保健医療分野における基礎研究推進事業（医薬基盤研究所）
2006.09～2007.03, 代表者：西田基宏, 九州大学薬学部, 日本
心臓の線維化形成に関わるシグナル経路の解明および線維化抑制薬探索に向けた新しいスクリーニング系を構築する。.

主要著書

1.

Nishida M, Sunggip C, Kitajima N & Kurose H, Angiotensin: New Research, Redox regulation of angiotensin receptor signaling in the heart., NOVA Publishers (New York), 2012.03.

2.

Nishida M, Ohba M, Nakaya M & Kurose H., Heart Failure: Symptoms, Causes and Treatment Options, NOVA Publishers (New York), 2011.03, Structural remodeling of the heart, including myocardial hypertrophy and fibrosis, is a key determinant for the clinical outcome of heart failure. A variety of evidence indicates the importance of neurohumoral factors, such as endothelin-1, angiotensin II, and norepinephrine for the initial phase of the development of cardiac remodeling. These agonists stimulate seven transmembrane spanning receptors that are coupled to heterotrimeric GTP-binding proteins (G proteins) of the Gi, Gq and G12 subfamilies. The pathophysiological roles of each G protein-mediated signaling have been revealed by studies using transgenic and knockout mice. Using specific pharmacological tools to assess the involvement of G protein signaling pathways, we have found that diacylglycerol-activated transient receptor potential canonical (TRPC) channels (TRPC3 and TRPC6), one of the downstream effectors regulated by Gαq, work as a key mediator in the development of cardiac hypertrophy. In contrast, we also revealed that activation of Gα12 family proteins in cardiomyocytes mediates pressure overload-induced cardiac fibrosis. Stimulation of purinergic P2Y6 receptors by extracellular nucleotides released by mechanical stretch is a trigger of Gα12-mediated fibrotic responses of the heart. Although cardiac fibrosis is believed to accompany with Gαq-mediated pathological hypertrophy that eventually results in heart failure, our results clearly show that cardiac fibrosis and hypertrophy are independent processes. These findings will provide a new insight into the molecular mechanisms underlying pathogenesis of heart failure..

主要原著論文

1.	西田 基宏, The purinergic P2Y6 receptor heterodimerizes with the angiotensin AT1 receptor to promote angiotensin II-induced hypertension, Science Signaling, doi: 10.1126/scisignal.aac9187., Vol. 9, Issue 411, ra7, 2016.01, The angiotensin (Ang) type 1 receptor (AT1R) promotes functional and structural integrity of the arterial wall to contribute to vascular homeostasis, but this receptor also promotes hypertension. In our investigation of how Ang II signals are converted by the AT1R from physiological to pathological outputs, we found that the purinergic P2Y6 receptor (P2Y6R), an inflammation-inducible G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptor (GPCR), promoted Ang II–induced hypertension in mice. In mice, deletion of P2Y6R attenuated Ang II–induced increase in blood pressure, vascular remodeling, oxidative stress, and endothelial dysfunction. AT1R and P2Y6R formed stable heterodimers, which enhanced G protein–dependent vascular hypertrophy but reduced β-arrestin–dependent AT1R internalization. Pharmacological disruption of AT1R-P2Y6R heterodimers by the P2Y6R antagonist MRS2578 suppressed Ang II–induced hypertension in mice. Furthermore, P2Y6R abundance increased with age in vascular smooth muscle cells. The increased abundance of P2Y6R converted AT1R-stimulated signaling in vascular smooth muscle cells from β-arrestin–dependent proliferation to G protein–dependent hypertrophy. These results suggest that increased formation of AT1R-P2Y6R heterodimers with age may increase the likelihood of hypertension induced by Ang II..
2.	Nishida M, Ogushi M, Suda R, Toyotaka M, Saiki S, Kitajima N, Nakaya M, Kim K-M, Ide T, Sato Y, Inoue K and Kurose H, Heterologous down-regulation of angiotensin type1 receptors by purinergic P2Y2 receptor stimulation through S-nitrosylation of NF-kB., Proc. Natl. Acad. Sci. USA., 10.1073/pnas.1017640108, 108, 6662-6667, 2011.04.
3.	Kinoshita H, Kuwahara K, Nishida M, Jiang Z, Rong X, Kiyonaka S, Kuwabara Y, Kurose H, Inoue R, Mori Y, Li Y, Nakagawa Y, Usami S, Fujiwara M, Yamada Y, Minami T, Ueshima K and Nakao K., Inhibition of TRPC6 channel activity contributes to the anti-hypertrophic effects of natriuretic peptides-guanylyl cyclase-A signaling in the heart., Circulation Research, in press, 2010.06.
4.	Nishida M, Maruyama Y, Tanaka R, Kontani K, Nagao T, & Kurose H, Gai and Gao are target proteins of reactive oxygen species., Nature, 408, 492-495, 2000.12.
5.	Nishida M, Urushidani T, Sakamoto K & Nagao T, l-cis Diltiazem attenuates intracellular Ca2+ overload by metabolic inhibition in guinea pig myocytes., The European Journal of Pharmacology, 385, 225-230, 1999.12.
6.	Nishida M, Nagao T & Kurose H, Activation of Rac1 increases c-Jun NH2-terminal kinase activity and DNA fragmentation in a calcium-dependent manner in rat myoblast cell line H9c2., Biochemical and Biophysical Research Communication, 262, 350-354, 1999.08.
7.	Nishida M, Sakamoto K, Urushidani T & Nagao T, Treatment with l-cis diltiazem before reperfusion reduces infarct size in the ischemic rabbit heart in vivo., The Journal of Pharmaceutical Sciences, 80, 319-325, 1999.07.

主要総説, 論評, 解説, 書評, 報告書等

1.	Nishida M, Kitajima N, Saiki S, Nakaya M & Kurose H, Regulation of angiotensin II receptor signaling by cysteine modification of NF-kB., Nitric Oxide, 2011.08, [URL].
2.	Nishida M, Roles of heterotrimetric GTP-binding proteins in the progression of heart failure., J. Pharmacol. Sci., 2011.06, [URL].
3.	西田基宏, 齊木翔太, 北島直幸, 仲矢道雄, 佐藤陽治, 黒瀬等, TRPCチャネルのリン酸化による心血管機能制御, 2010.12.
4.	西田基宏, 黒瀬等, アンジオテンシンIIと活性酸素シグナル, 2010.10.
5.	西田基宏, 大場三奈, 仲矢道雄, 黒瀬等, 三量体Ｇ蛋白質シグナリングを介した心不全発症の分子機構, 2010.05.
6.	西田基宏, 渡辺健太, 仲矢道雄, 黒瀬等, ジアシルグリセロール感受性TRPCチャネルを介した心肥大誘導のメカニズム, 2010.03.
7.	西田基宏, 佐藤陽治, 仲矢道雄, 黒瀬等, Gタンパク質共役型受容体－TRPCチャネルタンパク複合体形成による心肥大シグナル制御, 2009.09.
8.	西田基宏, 仲矢道雄, 黒瀬等, G12/13タンパク質による活性酸素シグナリング, 2009.09.
9.	西田基宏, 心不全治療の新たな標的としてのTRPCチャネル, 2008.08.
10.	Nishida M, Hara Y, Yoshida T, Inoue R & Mori Y., TRP channels: formation of signal complex and regulation of cellular functions, 2006.09.
11.	Mori Y, Nishida M, Shimizu S, Ishii M, Yoshinaga T, Ino M, Sawada K & Niidome T, Mice lacking the a1B subunit (CaV 2.2) reveals a predominant role of N-type Ca2+ channels in the sympathetic regulation of circulatory system., 2002.12.
12.	西田基宏, 長尾拓, 黒瀬等, 虚血障害とGタンパク質, 2001.04.
13.	Nishida M. , Heterotrimetric G protein signaling in Heart Failure. , J. Pharmacol. Sci., in press..

主要学会発表等

1.	西田 基宏, Regulation of cardiac oxygen remodeling via electrophilic modification of Drp1, The 89th Annual Meeting of the Japanese Biochemical Society, 2017.09.
2.	西田 基宏, New strategies for drug development of heart failure, Medical Research Seminar in Malaysia Sabah University, 2017.01.
3.	西田 基宏, Myocardial early senescence mediated by mitochondria-cytoskeleton interaction, The 39th Annual Meeting of the Molecular Biology Society of Japan, 2016.12, Myocardial early senescence mediated by mitochondria-cytoskeleton interaction.
4.	西田 基宏, TRPC channels in cardiovascular stress resilience, International and Interdisciplinary Symposium 2016 “Towards a New Era of Cardiovascular Research, 2016.07.
5.	西田 基宏, Redox regulation of G proteins in cardiac remodeling, The 9th International Conference on the Biology, Chemistry, and Therapeutic Applications of Nitric Oxide, 2016.05.
6.	西田基宏，北島直幸，仲矢道雄，黒瀬等, 心臓の線維化におけるジアシルグリセロール活性化型TRPCチャネルの役割, 日本薬理学会年会, 2012.03.
7.	西田基宏, 心臓リモデリングにおけるTRPCチャネルの役割, 細胞電気薬理研究会, 2012.03.
8.	Motohiro Nishida, Sulfhydration of electrophiles underlies protection against reactive oxygen species-mediated cardiac senescence by hydrogen sulfide., The 10th JBS Biofrontier Symposium -New aspects of phospholipid biology and medicine 2011, 2011.11.
9.	西田基宏, 心不全におけるＧ蛋白質の酸化修飾と硫化水素による制御, 千里ライフサイエンスセミナー「ストレス応答の分子メカニズム」, 2011.11.
10.	西田基宏, 心臓リモデリングにおける親電子修飾の役割と硫化水素による保護効果, 第２回日本学術振興会レドックス・ライフイノベーション第170委員会, 2011.07.
11.	西田基宏, Study on the role of heterotrimeric G protein signaling pathways for the treatment of heart failure, 第84回日本薬理学会年会, 2011.03.
12.	西田基宏、大串真理子、須田玲子、仲矢道雄、黒瀬等, 活性酸素／ＮＯシグナル複合体形成によるNF-kBの機能制御, 第33回日本分子生物学会年会・第83回日本生化学会大会　合同大会BMB2010, 2010.12.
13.	Nishida M, Ogushi M, Suda R, Nakaya M & Kurose H., ATP decreases angiotensin type 1 receptor expression through S-nitrosylation of nuclear factor kB., The 6th international conference on the biology, chemistry, and therapeutic applications of nitric oxide (NO2010), 2010.06, Expression of Angiotensin (Ang) II type 1 receptor (AT1R) is one of major factors that determine Ang II-induced cardiovascular functions. We here demonstrated that AT1R-induced increase in intracellular Ca2+ concentration ([Ca2+]i increase) is inhibited by ATP treatment in rat cardiac fibroblasts. The number of AT1R was decreased by ATP. ATP increased nuclear factor of activated T cells (NFAT) activity through P2Y2 receptor. NFAT activation increased the expression of inducible nitric oxide synthase (iNOS), and the suppression of AT1R-induced [Ca2+]i increase by ATP was canceled by the inhibition of iNOS. Expression of AT1R is regulated by NF-κB activity and iNOS-induced NO inhibits NF-κB activity through S-nitrosylation of p65 subunit of NF-κB at Cys38. The suppression of AT1R-induced [Ca2+]i increase by ATP was canceled by overexpression of p65 (C38S) mutant. Furthermore, p65 was coprecipitated with iNOS and inhibition of p65-iNOS interaction canceled the S-nitrosylation of p65 induced by ATP stimulation. These results suggest that locally generated NO leads to S-nitrosylation of p65 at Cys38 via interaction of p65 with iNOS proteins, and S-nitrosylation of p65 underlies heterologous down-regulation of AT1R by purinergic P2Y2 receptor stimulation in rat cardiac fibroblasts..
14.	Nishida M, Kitajima N, Nakaya M, Ide T, Sato Y & Kurose H., Inhibition of phosphodiesterase 5 prevents cardiac hypertrophy through phosphorylation of TRPC6 at Thr69., XX World Congress of the International Society for Heart Research 2010 Kyoto (ISHR2010), 2010.05.
15.	西田基宏，西岡絹恵，有吉麻里奈，仲矢道雄，黒瀬等, TRPCチャネルのリン酸化による血管緊張性の制御, 日本薬学会第130年会, 2010.03.
16.	西田基宏，黒瀬等，渡辺健太，清中茂樹，森泰生, 心肥大を仲介するTRPCチャネル, 第83回日本薬理学会年会, 2010.03.
17.	西田基宏，仲矢道雄，黒瀬等, Ｓ－ニトロシル化修飾によるアンジオテンシン受容体シグナリングの調節, 第83回日本薬理学会年会, 2010.03.
18.	西田基宏, 心不全を制御する三量体Ｇ蛋白質, 京都大学先端医工学研究ユニットＨ21年度研究発表交流会, 2010.03.
19.	Nishida M, Diacylglycerol-activated TRPC channels as a new therapeutic target of heart failure., The 9th International Symposium on ‘Recent Trends in Pharmaceutical Sciences’., 2010.02, In excitable cardiomyocytes, changes in the frequency, shape, or amplitude of Ca2+ transients evoked by Ca2+ influx-induced Ca2+ release have been suggested to encode signals for induction of hypertrophy. A partial depolarization of plasma membrane by receptor stimulation is reported to increase the frequency of Ca2+ oscillations leading to activation of the nuclear factor of activated T cells (NFAT), a hypertrophic transcription factor that is predominantly regulated by calcineurin. Canonical transient receptor potential (TRPC) subfamily proteins were recently identified as a molecular candidate of receptor-activated cation channels. Among 7 TRPC homologues (C1-C7), diacylglycerol (DAG)-activated TRPC channels (C3, C6, C7) have been implicated in agonist-induced membrane depolarization in vascular systems. It has been thought that the sustained increase in intracellular Ca2+ concentration ([Ca2+]i) for hypertrophy occurs via Gq-stimulated production of inositol-1,4,5-trisphosphate (IP3) and IP3-mediated release of Ca2+ from intracellular store. However, we found that DAG-activated TRPC3 and TRPC6 channels are responsible for agonist-induced membrane depolarization in rat neonatal cardiomyocytes. As inhibition of either TRPC3 or TRPC6 completely suppressed agonist-induced NFAT activation and hypertrophic responses, TRPC3 and TRPC6 may form a heterotetramer channels. In addition, treatment with a TRPC3-selective blocker, pyrazole-3, attenuates pressure overload-induced cardiac hypertrophy and impairment of left ventricular function in mice. As TRPC channels participate in pathological hypertrophy but not physiological contraction and the relaxation cycle, these results suggest that DAG-activated TPRC channels are a new target for the treatment of heart failure..
20.	Nishida M, Role of diacylglycerol-activated TRPC channels in the development of heart failure., The 6th Japan-Korea Conference on Cellular Signaling for Young Scientists., 2009.11, In excitable cardiomyocytes, changes in the frequency, shape, or amplitude of Ca2+ transients evoked by Ca2+ influx-induced Ca2+ release have been suggested to encode signals for induction of hypertrophy. A partial depolarization of plasma membrane by receptor stimulation is reported to increase the frequency of Ca2+ oscillations leading to activation of the nuclear factor of activated T cells (NFAT), a hypertrophic transcription factor that is predominantly regulated by calcineurin. Canonical transient receptor potential (TRPC) subfamily proteins were recently identified as a molecular candidate of receptor-activated cation channels. Among 7 TRPC homologues (C1-C7), diacylglycerol (DAG)-activated TRPC channels (C3, C6, C7) have been implicated in agonist-induced membrane depolarization in vascular systems. It has been thought that the sustained increase in intracellular Ca2+ concentration ([Ca2+]i) for hypertrophy occurs via Gq-stimulated production of inositol-1,4,5-trisphosphate (IP3) and IP3-mediated release of Ca2+ from intracellular store. However, we found that DAG-activated TRPC3 and TRPC6 channels are responsible for agonist-induced membrane depolarization in rat neonatal cardiomyocytes. As inhibition of either TRPC3 or TRPC6 completely suppressed agonist-induced NFAT activation and hypertrophic responses, TRPC3 and TRPC6 may form a heterotetramer channels. In addition, treatment with a TRPC3-selective blocker, pyrazole-3, attenuates pressure overload-induced cardiac hypertrophy and impairment of left ventricular function in mice. As TRPC channels participate in pathological hypertrophy but not physiological contraction and the relaxation cycle, these results suggest that DAG-activated TPRC channels are a new target for the treatment of heart failure..
21.	Nishida M, Down-regulation of angiotensin receptors by S-nitrosylation of NF-κB., Society for Free Radical Research (SFRR) International., 2009.09.
22.	Nishida M, TRPC channels as a new therapeutic target for heart failure., The 36th Congress of the International Union of Physiological Sciences (IUPS2009), 2009.07.
23.	Nishida M, Sato Y, Uemura A, Tozaki-Saitoh H, Nakaya M, Inoue K & Kurose H., P2Y6 receptor-Gα12/13 signaling triggers pressure overload-induced cardiac fibrosis., Fukuoka Purine 2009 (Joint with JSPS Core-to-Core Program A Satellite Symposium for IUPS2009), 2009.07.
24.	西田基宏、佐藤陽治、井上隆司、森泰生、黒瀬等, 心臓の病的肥大におけるTRPCチャネルの役割, 日本薬学会第129年会, 2009.03.
25.	西田基宏、佐藤陽治、仲矢道雄、井上隆司、森泰生、黒瀬等, 受容体－TRPCチャネルの機能的共役による心肥大シグナル制御, 第82回日本薬理学会年会, 2009.03.
26.	Motohiro Nishida, Extracellular nucleotides trigger pressure overload-induced cardiac fibrosis through P2Y6R-Galpha12/13 signaling pathways., KUSCR Japan/Korea Conference on Cellular Signaling 2008, 2008.12.
27.	西田基宏、大串真理子、須田玲子、仲矢道雄、黒瀬等, S-ニトロシル化修飾によるアンジオテンシン受容体の調節機構, 生化学会・分子生物学会合同大会BMB2008, 2008.12.

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