トランスジェニックマウスを使ったヒスタミン産生細胞の病態解析

• Project/Area Number: 26460332
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Tohoku University
• Principal Investigator: 大津 浩 東北大学, 工学(系)研究科(研究院), 教授 (60250742)
• Co-Investigator(Kenkyū-buntansha): 平澤 典保 東北大学, 薬学研究科(研究院), 教授 (80181155)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Discontinued (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: ヒスタミン / ヒスチジン脱炭酸酵素(HDC) / HDC-KOマウス / ヒスタミン産生細胞 / トランスジェニックマウス / アレルギー / レポーターマウス / 蛍光

Outline of Annual Research Achievements

ヒスタミンの生体内での産生源を明らかにすべくヒスチジン脱炭酸酵素（HDC）遺伝子の発現をモニターするレポーターマウスを作製した。ヒスタミンは必須アミノ酸の一種であるヒスチジンから生体内唯一の酵素であるHDCを介して産生されるため、この遺伝子の発現をモニターすることによりヒスタミンの産生について考察できる。まずHDC遺伝子の含まれるBAC　(bacterial artificial chromosome)　クローンを鋳型として、HDC遺伝子の一部を増幅し、pGEM-T vectorに導入し、このプラスミッド内で遺伝子改変をおこなった。その後、BACとの間で相同組み換えを利用して、第一エクソン部位にGFPを挿入したBACを準備し、このコンストラクトをマウス受精卵に打ち込みトランスジェニックマウスを用意した。このマウスが脳視床下部や胃体部におけるGFP発現は免疫染色で確認しているがHDC産生細胞と一致しているかどうかについて確認が必要である。そこで本研究ではレポーターマウスから摘出した胃におけるGFPとHDCの免疫染色を遂行し、染色パターンはGFPとHDCで一致していることが判明した。また小腸壁での細胞においては、肥満細胞の他に、好酸球や好塩基球にも蛍光の発光がみられ、現在まで考えられていた以上に多種類の血液細胞にヒスタミンが存在する可能性が出てきている。このため、今後様々な病態モデルを使った実験においても新たなヒスタミン産生細胞を認める可能性が高いと考え、今後も引き続いて他施設にて評価されていくことになると考えている。

Research Products

• [Journal Article] Critical role of endogenous histamine in promoting end-organ tissue injury in sepsis. (2016)
  • Author(s): Hattori M, Yamazaki M, Ohashi W, Tanaka S, Hattori K, Todoroki K, Fujimori T, Ohtsu H, Matsuda N, Hattori Y.
  • Journal Title: Intensive Care Med Exp. Volume: ４ Issue: 1 Pages: 36-44
  • DOI: 10.1186/s40635-016-0109-y
  • Peer Reviewed / Open Access
• [Journal Article] Deficiency of histidine decarboxylase attenuates peripheral nerve fibre elongation into the epidermis in surfactant-treated mouse skin. (2016)
  • Author(s): Inami Y, Sato A, Ohtsu H, Mano Y, Sasaki A, Kuraishi Y, Andoh T.
  • Journal Title: Exp Dermatol. Volume: - Issue: 5 Pages: 441-443
  • DOI: 10.1111/exd.13223
  • Peer Reviewed
• [Journal Article] Effect of mineralocorticoid receptor antagonists on proteinuria and progression of chronic kidney disease: a systematic review and meta-analysis. (2016)
  • Author(s): Currie G, Taylor AH, Fujita T, Ohtsu H, Lindhardt M, Rossing P, Boesby L, Edwards NC, Ferro CJ, Townend JN, van den Meiracker AH, Saklayen MG, Oveisi S, Jardine AG, Delles C, Preiss DJ, Mark PB.
  • Journal Title: BMC Nephrol. Volume: 17 Issue: 1 Pages: 127-140
  • DOI: 10.1186/s12882-016-0337-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Histamine regulation of microglia: Gene-environment interaction in the regulation of central nervous system inflammation. (2016)
  • Author(s): Frick L, Rapanelli M, Abbasi E, Ohtsu H, Pittenger C.
  • Journal Title: Brain Behav Immun. Volume: 57 Pages: 326-337
  • DOI: 10.1016/j.bbi.2016.07.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High-amplitude theta wave bursts characterizing narcoleptic mice and patients are also produced by histamine deficiency in mice. (2016)
  • Author(s): Bastianini S, Lo Martire V, Berteotti C, Silvani A, Ohtsu H, Lin JS, Zoccoli G.
  • Journal Title: J Sleep Res. Volume: 25 Issue: 5 Pages: 591-595
  • DOI: 10.1111/jsr.12404
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mast cell histamine-mediated transient inflammation following exposure to nickel promotes nickel allergy in mice (2016)
  • Author(s): Kinbara M, Bando K, Shiraishi D, Kuroishi T, Nagai Y, Ohtsu H, Takano-Yamamoto T, Sugawara S, Endo Y
  • Journal Title: Exp Dermatol. Volume: 印刷中 Issue: 6 Pages: 466-71
  • DOI: 10.1111/exd.12985
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Crosstalk Between Histamine and T Cells in Allergic Disease. (2016)
  • Author(s): Mayumi Saeki, Tomoe Nishimura, Osamu Kaminuma, Hiroshi Ohtsu, Akio Mori and Takachika Hiroi.
  • Journal Title: Current Immunology Reviews Volume: 12 Pages: 10-13
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Histamine Transmission Modulates the Phenotype of Murine Narcolepsy Caused by Orexin Neuron Deficiency (2015)
  • Author(s): Stefano Bastianini; Alessandro Silvani; Chiara Berteotti; Viviana Lo Martire; Gary Cohen; Hiroshi Ohtsu; Jian-Sheng Lin; Giovanna Zoccoli.
  • Journal Title: PLoS One Volume: 10 Issue: 10 Pages: e0140520-e0140520
  • DOI: 10.1371/journal.pone.0140520
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Large particulate allergens can elicit mast cell-mediated anaphylaxis without exit from blood vessels as efficiently as do small soluble allergens (2015)
  • Author(s): LiHua Li, Takuya Ohta, Kayo Horiguchi, Yohei Kawano, Hiroshi Ohtsu, Yoshinori Yamanishi, MD., Hajime Karasuyama.
  • Journal Title: Biochem Biophys Res Commun Volume: 467 Issue: 1 Pages: 70-75
  • DOI: 10.1016/j.bbrc.2015.09.120
  • Peer Reviewed
• [Journal Article] Histidine decarboxylase knockout mice, a genetic model of Tourette syndrome, show repetitive grooming after induced fear. (2015)
  • Author(s): Xu M, Li L, Ohtsu H, Pittenger C.
  • Journal Title: Neurosci Lett. Volume: 595 Pages: 50-53
  • DOI: 10.1016/j.neulet.2015.03.067
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Histamine Promotes Locomotion Recovery After Spinal Cord Hemisection via Inhibiting Astrocytic Scar Formation. (2015)
  • Author(s): Zhao YY, Yuan Y, Chen Y, Jiang L, Liao RJ, Wang L, Zhang XN, Ohtsu H, Hu WW, Chen Z.
  • Journal Title: CNS Neurosci. Ther Volume: 21 Issue: 5 Pages: 454-62
  • DOI: 10.1111/cns.12379
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Histamine suppresses regulatory T cells mediated by TGF-β in murine chronic allergic contact dermatitis. (2015)
  • Author(s): Kyoko Tamaka, Masahiro Seike, Tamio Hagiwara, Atsushi Sato, Hiroshi Ohtsu.
  • Journal Title: Exp Dermatol Volume: 24 Issue: 4 Pages: 280-284
  • DOI: 10.1111/exd.12644
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Protective effect of carnosine on febrile seizures in immature mice. (2015)
  • Author(s): Dai Y, Wu D, Feng B, Hou W, Xu C, Ohtsu H, Chen Z, Hu W.
  • Journal Title: Neurosci Lett Volume: 588 Pages: 95-100
  • DOI: 10.1016/j.neulet.2014.12.061
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The role of histamine in the retina, studies on the HDC knockout mouse. (2015)
  • Author(s): U Greferath, KA Vessey, AI Jobling, SA Mills, BV Bui, Z He, H Ohtsu , EL Fletcher.
  • Journal Title: PLoS One Volume: 9 Issue: 12 Pages: e116025-e116025
  • DOI: 10.1371/journal.pone.0116025
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dysregulated intracellular signaling in the striatum in a pathophysiologically grounded model of Tourette syndrome. (2014)
  • Author(s): Maximiliano Rapanelli, Luciana R. Frick, Vladimir Pogorelov, Kristie T. Ota, Eeman Abbasi, Hiroshi Ohtsu, Christopher Pittenger.
  • Journal Title: European Neuropsychopharmacology Volume: 24 Issue: 12 Pages: 1896-1906
  • DOI: 10.1016/j.euroneuro.2014.10.007
  • Peer Reviewed
• [Journal Article] Close relationship between T helper (Th)17 and Th2 response in murine allergic contact dermatitis. (2014)
  • Author(s): A. Matsushita, M. Seike, T. Hagiwara, A. Sato and H. Ohtsu
  • Journal Title: Clin Exp Dermatol Volume: 39 Issue: 8 Pages: 924-931
  • DOI: 10.1111/ced.12425
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Roles of histamine on the expression of aldehyde dehydrogenase 1 in endometrioid adenocarcinoma cell line. (2014)
  • Author(s): Wang Y, Jiang Y, Ikeda J, Tian T, Sato A, Ohtsu H, Morii E .
  • Journal Title: Cancer Medicine Volume: 3 Issue: 5 Pages: 1126-1135
  • DOI: 10.1002/cam4.296
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Histamine H3 Receptors Aggravate Cerebral Ischemic Injury by Histamine-independent Mechanisms. (2014)
  • Author(s): Haijing Yan, Xiangnan Zhang, Weiwei Hu, Jing Ma, Weiwei Hou, Xingzhou Zhang, Xiaofen Wang, Jieqiong Gao, Yao Shen, Jianxin Lu, Hiroshi Ohtsu, Feng Han, Guanghui Wang, and Zhong Chen.
  • Journal Title: Nature Communications Volume: 5 Issue: 1 Pages: 33334-33334
  • DOI: 10.1038/ncomms4334
  • Peer Reviewed
• [Journal Article] Histidine decarboxylase deficiency causes Tourette syndrome: parallel findings in humans and mice. (2014)
  • Author(s): L C Baldan, K A. Williams, J-D Gallezot, V Pogorelov, M Rapanelli, M Crowley, GM. Anderson, E Loring, R Gorczyca, E Billingslea, S Wasylink, KE. Panza, A. G Ercan-Sencicek, K Krusong, B L. Leventhal, Ohtsu, ZA. Hughes, JH. Krystal, Linda Mayes, I de Araujo, Y-S Ding, MW. State, C Pittenger.
  • Journal Title: Neuron Volume: 81 Issue: 1 Pages: 77-90
  • DOI: 10.1016/j.neuron.2013.10.052
  • Peer Reviewed
• [Journal Article] Histamine synthesis is required for granule maturation in murine mast cells. (2014)
  • Author(s): Nakazawa, S., Sakanaka, M., Furuta, K., Natsuhara, M., Takano, H., Tsuchiya, S., Okuno, Y., Ohtsu, H., Nishibori, M., Thurmond, R.L., Hirasawa, N., Nakayama, K., Ichikawa, A., Sugimoto, Y., and Tanaka, S.
  • Journal Title: Eur. J. Immunol. Volume: 44 Issue: 1 Pages: 204-214
  • DOI: 10.1002/eji.201343838
  • Peer Reviewed
• [Presentation] 産学連携による福祉機器の開発 (2015)
  • Author(s): 大津 浩
  • Organizer: 日本褥瘡学会
  • Place of Presentation: 仙台国際会議場（宮城県、仙台市）
  • Year and Date: 2015-08-28
  • Invited
• [Presentation] New findings of a histamine-related pathological phenomenon and its therapeutic application (2015)
  • Author(s): 大津 浩
  • Organizer: 日本薬理学会
  • Place of Presentation: 名古屋国際会議場（愛知県、名古屋市）
  • Year and Date: 2015-03-18
• [Book] Handbook of Experimental Pharmacology ( Histamine and Histamine Receptors in Allergic Dermatitis.) (2016)
  • Author(s): Ohtsu H, Seike M
  • Publisher: Springer
• [Book] Handbook of Experimental Pharmacology (2016)
  • Author(s): Hiroshi Ohtsu, Masahiro Seike
  • Publisher: Springer
• [Remarks] ようこそ
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• [Remarks]
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