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１．神経堤細胞の異常に起因する疾患の分子遺伝学的解析２．腸管神経系と腸管免疫系の相互作用 ３．遺伝子組み換えマウスを用いた細胞増殖・分化の分子機構の解析 ４．その他、他大学・研究所との共同研究による各種疾患モデルマウスの作製・解析 |
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「疾患モデルマウスを用いたミクロ分子からマクロ病態への解析」 １．p38の病態生理的役割の解明 ２．神経変性疾患におけるカルシウムチャネルの機能 |
「幡野グループの研究内容」
「粕谷グループの研究内容」
p38 MAPK（mitogen-activated protein kinase）は、ストレスや炎症性サイトカインにより活性化されるMAPKファミリーであり、別名、stress-activated protein kinase（SAPK）とも呼ばれている。p38は炎症性サイトカインやケモカインの産生制御に深く関わっており、炎症性疾患の創薬ターゲットとして注目を集めている。我々は、p38ノックアウトマウスおよびトランスジェニックマウスを用いて、様々な炎症性疾患におけるp38の関与様式を探るとともに、特に、根治療法の存在しない疾患の新たな治療法を探るべく研究を行っている。
＜関連文献等＞
1) Possible involvement of p38 mitogen-activated protein kinase in decidual function in parturition. Takanami-Ohnishi Y., et al., Biochem Biophys Res Commun 288: 1155-1161 2002.
2) Essential role of p38 mitogen-activated protein kinase in contact hypersensitivity. Takanami-Ohnishi Y., et al., J Biol Chem 277: 37896-37903, 2002.
3) 「接触皮膚炎へのp38 mitogen-activated protein kinase の関与機構の解明」 粕谷善俊, http://www.cosmetology.or.jp/2003/11-15.pdf
4) Role of p38 mitogen-activated protein kinase in thrombus formation. Sakurai K., et al., J Recept Signal Transduct 24: 283-296 2004.
5) 「外部環境因子により発症する慢性閉塞性肺疾患の分子解析」 粕谷善俊, http://www.nissan-zaidan.or.jp/membership/2004/05_seika/0014.pdf
6) Involvement of p38alpha mitogen-activated protein kinase in lung metastasis of tumor cells. Matsuo Y., et al., J Biol Chem 281: 36767-36775, 2006.
7) “nvolvement of p38alpha in kainate-induced seizure and neuronal cell damage. Namiki K., et al., J Recept Signal Transduct 27: 99-111, 2007.
8) 「p38阻害剤」 粕谷善俊, 他, 日本薬理学会誌 133: 357-359, 2009.
9) Mechanism of p38alpha-mediated experimental autoimmune encephalomymyelitis. Namiki K, et al., J Biol Chem. 287: 24228-24238, 2012.
10) Amano H, Murata K, Matsunaga H, Tanaka K, Yoshioka K, Kobayashi T, Ishida J, Fukamizu A, Sugiyama F, Sudo T, Kimura S, Tatsumi K, Kasuya Y: p38 Mitogen-Activated Protein Kinase Accelerates Emphysema in Mouse Model of Chronic Obstructive Pulmonary Disease. J Recept Signal Transduct. 34(4):299-306, 2014.
11) p38MAPK阻害剤，粕谷善俊：最新関節リウマチ学 -寛解・治療を目指した研究と最新治療- 日本臨床 72：525-529, 2014.
12）p38の機能と阻害薬の動向 粕谷善俊 日本薬理学会誌 145: 21-26, 2015.
＜関連文献等＞
1) The utilization of gene targeting models during in preclinical study of drug discovery process--example of phenotypic and functional analysis of Cacna1beta gene product. Miyamoto N., et al., Curr Pharm Biotechnol 10 261-267 2009.
2) N-type calcium channel in the pathogenesis of experimental autoimmune encephalomyelitis. Tokuhara N, Namiki K, Uesugi M, Miyamoto C, Ohgoh M, Ido K, Yoshinaga T, Yamauchi T, Kuromitsu J, Kimura S, Miyamoto N, Kasuya Y:J. Biol. Chem. 285(43):33294-33306, 2010.
3) Cacna1beta-deficient mice resistant to brain injury, Kasuya Y., et al., 2012 in preparation.
上記の研究内容も含め、理化学研究所、筑波大学、（株）エーザイ、（株）宇部興産、等の他機関とネットワークを構築し、活発な議論を持ちながら共同研究を行っている。また、p38にとどまらず、細胞内リン酸化酵素の機能解析を始めとした細胞内情報伝達系の研究にも参加している。
＜関連文献等＞
1) Laminin alpha 3 LG4 module induces matrix metalloproteinase-1 through mitogen-activated protein kinase signaling. Utani A., et al., J Biol Chem 278: 34483-3449, 2003.
2) Endothelin-1-induced cardiac hypertrophy is inhibited by activation of peroxisome proliferator-activated receptor-alpha partly via blockade of c-Jun NH2-terminal kinase pathway. Irukayama-Tomobe Y., et al., Circulation 109: 904-910, 2004.
3) Regulatory roles for APJ, a seven-transmembrane receptor related to angiotensin-type 1 receptor in blood pressure in vivo. Ishida J., et al., J Biol Chem 279: 26274-26279, 2004.
4) Neurochondrin negatively regulates CaMKII phosphorylation, and nervous system-specific gene disruption results in epileptic seizure. Dateki M., et al., J Biol Chem 280: 20503-20508, 2005.
5) Activation pattern of MAPK signaling in the hearts of trained and untrained rats following a single bout of exercise. Iemitsu M., et al., J Appl Physiol 101: 151-163, 2006.
6) Mitogen-activated protein kinases, Erk and p38, phosphorylate and regulate Foxo1. Asada S., et al., Cell Signal 19: 519-527 2007.
7) Oxidative stress-induced ubiquitination of RCAN1 mediated by SCFbeta-TrCP ubiquitin ligase. Asada S., et al., Int J Mol Med 22: 95-104, 2008.
8) Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt. Yamagata K., et al., Mol Cell 32: 221-231, 2008.
9) Impaired Placental Neovascularization in Mice with Pregnancy-Associated Hypertension. Furuya M, et al., Laboratory Investigation, 88(4): 416-429, 2008.
10) The utilization of gene targeting models during in preclinical study of drug discovery process -Example of phenotypic and functional analysis of Cacna1b gene product- Miyamoto N, et al., Curr. Pharmaceut. Biotech. 10(2):261-267, 2009.
11) Cigarette smoke-induced pulmonary inflammation is attenuated in CD69-deficient mice. Tsuyusaki J, et al., J . Receptor Signal Transduct. 31(6):434-439, 2011.
12) Attenuation of lung inflammation and fibrosis in CD69-deficient mice after intratracheal bleomycin. Yamauchi K, et al.,Respir. Res. Oct 5;12:131., 2011.
13) Functional analysis of guinea pig beta1-adrenoceptor. Tanaka Y, et al., J Receptor Signal Transduct. 31(6):395-401, 2011.
14) Mechanism for p38alpha-mediated experimental autoimmune encephalomyelitis. Namiki K, et al., J. Biol. Chem. 287(29): 24228-24238, 2012.
15) Role of CD69 in acute lung injury. Ishizaki S,et al., Life Sci. 90(17-18): 657-665, 2012.
16) Endothelin B receptor-mediated encephalopathic events in mouse sepsis model. Naito Y, et al., Life Sci, 24;118(2):340-346, 2014.
17) Endothelin regulates function of IL-17-producing T cell subset. Tanaka K, et al., Life Sci. 118(2):244-247, 2014.
18) Therapeutic effect of lung mixed culture-derived epithelial cells on lung fibrosis. Tanaka K, et al., Laboratory Investigation, 94(11):1247-1259, 2014.
19) p38 Mitogen-Activated Protein Kinase Accelerates Emphysema in Mouse Model of Chronic Obstructive Pulmonary Disease. Amano H, et al., J Recept Signal Transduct. 34(4):299-306, 2014.