Elucidation of mechanisms of peripheral itch hypersensitivity focusing on dorsal root ganglia and development for its therapeutic application

2016 Fiscal Year Research-status Report

• Project/Area Number: 16K08997
• Research Institution: Juntendo University
• Principal Investigator: 高森 建二 順天堂大学, 医学部, 特任教授 (40053144)
• Co-Investigator(Kenkyū-buntansha): 冨永 光俊 順天堂大学, 医学(系)研究科(研究院), 准教授 (50468592) ; 鎌田 弥生 順天堂大学, 医学(系)研究科(研究院), 非常勤助教 (00410035) ; 梅原 芳恵 順天堂大学, 医学(系)研究科(研究院), 特任研究員 (40707072)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: サテライトグリア / 難治性かゆみ / アトピー性皮膚炎 / 後根神経節

Outline of Annual Research Achievements

本年度は、アトピー性皮膚炎（AD）のDRGにおいてかゆみに関与する新規分子を発見することを目的とした。AD様病態を誘発しないNC/Ngaマウス（Controlマウス）と比較し、AD様病態を発症させたNC/Ngaマウス（AD-NC/Nga）のDRGではかゆみ関連受容体（IL-31RA及びNK1R）及びsatellite glial cell (SGC)マーカー（GFAP）遺伝子の発現量が増加することを見出した。また、Control及びADマウスのDRGから抽出したタンパク質溶液をサイトカインアレイに供した結果、リポカリン2（LCN2）の増加が認められた。免疫組織学化学法によりDRGにおけるLCN2の発現部位を検討した結果、SGCに特異的に発現することが明らかとなった。また、ControlマウスのSGCと比較して、ADマウスのSGCではLCN2陽性SGCの割合が有意に増加した。さらに、ADマウスのDRG細胞において、LCN2の受容体の一つである24p3Rの発現が認められた。近年、LCN2は脊髄レベルでADのかゆみの増強に関与することが報告されていることから、SGC由来のLCN2もADにおけるかゆみの増強に関与することが示唆された。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

本年度は、AD-NC/NgaマウスのDRGで発現増加するかゆみ関連分子LCN2の同定とその発現細胞であるSGCを特定した。このことから、本年度は当初の計画通りに、おおむね順調に研究が進展したと考えられる。

Strategy for Future Research Activity

現在、培養DRG細胞にLCN2を添加することで、DRGにおけるかゆみ関連受容体の発現変動を検討中である。今後は、髄腔内LCN2投与マウスを用いて、かゆみ行動やその過敏性に対するLCN2の影響について検討する予定である。

Causes of Carryover

残額が14円では本研究に使用する物品を購入できないため。

Expenditure Plan for Carryover Budget

残額は平成29年度経費とともに物品費として使用する。

Research Products

• [Journal Article] Oral administration of milk-derived phospholipids inhibits a penetration of cutaneous nerve fibers into epidermis in an acute dry skin model mouse. (2017)
  • Author(s): Sakaguchi A, Kamata Y, Takahashi N, Matsuda H, Kosaka R, Umehara Y, Ogawa H, Tominaga M, Takamori K.
  • Journal Title: Clin Exp Dermatol Volume: 印刷中 Pages: 印刷中
  • DOI: -
  • Peer Reviewed
• [Journal Article] A possible role for CD26/DPPIV enzyme activity in the regulation of psoriatic pruritus. (2017)
  • Author(s): Komiya E, Hatano R, Otsuka H, Itoh T, Yamazaki H, Yamada T, Dang NH, Tominaga M, Suga Y, Kimura U, Takamori K, Morimoto C, Ohnuma K.
  • Journal Title: J Dermatol Sci Volume: 印刷中 Pages: 印刷中
  • DOI: doi.org/10.1016/j.jdermsci.2017.03.005
  • Peer Reviewed
• [Journal Article] Efficacy of an emollient containing diethylene glycol/dilinoleic acid copolymer for the treatment of dry skin and pruritus in patients with senile xerosis. (2017)
  • Author(s): Izumi R, Negi O, Suzuki T, Tominaga M, Kamo A, Suga Y, Matsukuma S, Takamori K.
  • Journal Title: J Cosmet Dermatol Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1111/jocd.12332
  • Peer Reviewed
• [Journal Article] Definition of Sensitive Skin: an Expert Position Paper from the Special Interest Group on Sensitive Skin of the International Forum for the Study of Itch. (2017)
  • Author(s): Misery L, Stander S, Szepietowski JC, Reich A, Wallengren J, Evers AW, Takamori K, Brenaut E, Gall-Ianotto CL, Fluhr J, Berardesca E, Weisshaar E.
  • Journal Title: Acta Derm Venereol. Volume: 97 Pages: 4-6
  • DOI: 10.2340/00015555-2397.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Accumulation of immunoglobulin G antibody against Dermatophagoides farina tropomyosin in dorsal root ganglia of NC/Nga mice with atopic dermatitis-like symptoms. (2017)
  • Author(s): Otsu A, Kawasaki H, Tominaga M, Shigenaga A, Matsuda H, Takahashi N, Nakajima T, Naito H, Baba T, Ogawa H, Tomooka Y, Yamakura F, Takamori K.
  • Journal Title: Biochem Biophys Res Commun Volume: 485 Pages: 707-712
  • DOI: 10.1016/j.bbrc.2017.02.109.
  • Peer Reviewed
• [Journal Article] Differences in therapeutic effects of topically applied corticosteroid and tacrolimus on atopic dermatitis-like symptoms in NC/Nga mice. (2017)
  • Author(s): Noguchi A, Tominaga M, Takahashi N, Matsuda H, Kamata Y, Umehara Y, Ko KC, Suga Y, Ogawa H, Takamori K.
  • Journal Title: J Dermatol Sci Volume: 86 Pages: 54-62
  • DOI: 10.1016/j.jdermsci.2016.12.015
  • Peer Reviewed
• [Journal Article] The effectiveness of new triple combination therapy using synthetic disease-modifying anti-rheumatic drugs with different pharmacological function against rheumatoid arthritis: the verification by an in vitro and clinical study. (2017)
  • Author(s): Hirai T, Ikeda K, Fujishiro M, Tsushima H, Hayakawa K, Suzuki S, Yamaguchi A, Nozawa K, Morimoto S, Takasaki Y, Ogawa H, Takamori K, Tamura N, Sekigawa I.
  • Journal Title: Clin Rheumatol Volume: 36 Pages: 51-58
  • DOI: 10.1007/s10067-016-3458-8.
  • Peer Reviewed
• [Journal Article] Efficacy of nalfurafine hydrochloride in patients with chronic liver disease with refractory pruritus: a randomized, double-blind trial. (2016)
  • Author(s): Kumada H, Miyakawa H, Muramatsu T, Ando N, Oh T, Takamori K, Nakamoto H.
  • Journal Title: Hepatol Res Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1111/hepr.12830.
  • Peer Reviewed
• [Journal Article] Relationships among plasma granzyme B level, pruritus and dermatitis in patients with atopic dermatitis. (2016)
  • Author(s): Kamata Y, Kimura U, Matsuda H, Tengara S, Kamo A, Umehara Y, Iizumi K, Kawasaki H, Suga Y, Ogawa H, Tominaga M, Takamori K.
  • Journal Title: J Dermatol Sci Volume: 84 Pages: 266-271
  • DOI: 10.1016/j.jdermsci.2016.09.009.
  • Peer Reviewed
• [Journal Article] Electrophysiological properties of brain-natriuretic peptide- and gastrin-releasing peptide-responsive dorsal horn neurons in spinal itch transmission. (2016)
  • Author(s): Kusube F, Tominaga M, Kawasaki H, Yamakura F, Naito H, Ogawa H, Tomooka Y, Takamori K.
  • Journal Title: Neurosci Lett Volume: 627 Pages: 51-60
  • DOI: 10.1016/j.neulet.2016.05.051.
  • Peer Reviewed
• [Journal Article] Intrathecal minocycline suppresses itch-related behavior and improves dermatitis in atopic dermatitis model mouse. (2016)
  • Author(s): Torigoe K, Tominaga M, Ko KC, Takahashi N, Matsuda H, Hayashi R, Ogawa H, Takamori K.
  • Journal Title: J Invest Dermatol Volume: 136 Pages: 879-881
  • DOI: 10.1016/j.jid.2015.12.037.
  • Peer Reviewed
• [Journal Article] Possible anti-pruritic mechanisms of cyclosporine A in atopic dermatitis. (2016)
  • Author(s): Ko KC, Tominaga M, Kamata Y, Umehara Y, Matsuda H, Takahashi N, Kina K, Ogawa M, Ogawa H, Takamori K.
  • Journal Title: Acta Derm Venereol Volume: 96 Pages: 624-629
  • DOI: 10.2340/00015555-2318.
  • Peer Reviewed / Open Access
• [Journal Article] Lipoarabinomannan binding to lactosylceramide in lipid rafts is essential for the phagocytosis of mycobacteria by human neutrophils. (2016)
  • Author(s): Nakayama H, Kurihara H, Morita YS, Kinoshita T, Mauri L, Prinetti A, Sonnino S, Yokoyama N, Ogawa H, Takamori K, Iwabuchi K.
  • Journal Title: Sci Signal Volume: 9 Pages: ra101
  • DOI: 10.1126/scisignal.aaf1585
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Spinal itch transmission. (2017)
  • Author(s): Takamori K.
  • Organizer: American Academy of Dermatology (AAD) 48th Annual Meeting
  • Place of Presentation: Convention center, Orland, FL, USA
  • Year and Date: 2017-03-02 – 2017-03-02
  • Int'l Joint Research / Invited
• [Presentation] 難治性かゆみと皮膚バリア機能. (2016)
  • Author(s): 高森建二、冨永光俊、須賀 康.
  • Organizer: 第46回日本皮膚アレルギー・接触皮膚炎学会総会学術大会
  • Place of Presentation: 京王プラザホテル（東京）
  • Year and Date: 2016-11-05 – 2016-11-06
  • Invited
• [Presentation] アトピー性皮膚炎、なぜかゆい？. (2016)
  • Author(s): 冨永光俊、高森建二.
  • Organizer: 第46回日本皮膚アレルギー・接触皮膚炎学会総会学術大会
  • Place of Presentation: 京王プラザホテル（東京）
  • Year and Date: 2016-11-05 – 2016-11-06
  • Invited
• [Presentation] 難治性かゆみのメカニズムと制御―皮膚から脊髄まで―. (2016)
  • Author(s): 冨永光俊、高森建二.
  • Organizer: 第26回国際痒みシンポジウム
  • Place of Presentation: エーザイ本社（東京）
  • Year and Date: 2016-10-08 – 2016-10-08
  • Invited
• [Presentation] Roles of brain-natriuretic peptide- and gastrin-releasing peptide-responsive neurons in spinal transmission of itch. (2016)
  • Author(s): Kusube Y, Tominaga M, Kawasaki H, Yamakura F, Naito H, Ogawa H, Tomooka Y, Takamori K.
  • Organizer: 46th Annual Meeting of the European Society for Dermatological Research (ESDR)
  • Place of Presentation: Technical University of Munich, Munich, Germany
  • Year and Date: 2016-09-07 – 2016-09-10
  • Int'l Joint Research
• [Presentation] Efficacy of kappa-opioid receptor agonist and mu-opioid receptor antagonist to treat itch in imiquimod-induced psoriasis-like dermatitis model. (2016)
  • Author(s): Takahashi, Tominaga M, Kamata Y, Umehara Y, Matsuda H, Ogawa H, Takamori K.
  • Organizer: 46th Annual Meeting of the European Society for Dermatological Research (ESDR)
  • Place of Presentation: Technical University of Munich, Munich, Germany
  • Year and Date: 2016-09-07 – 2016-09-10
  • Int'l Joint Research
• [Presentation] An analgesic agent suppresses itch-related behavior in NC/Nga mice with atopic dermatitis-like symptoms. (2016)
  • Author(s): Kamo A, Tominaga M, Matsuda H, Kina K, Kamata Y, Umehara Y, Ogawa H, Takamori K.
  • Organizer: 46th Annual Meeting of the European Society for Dermatological Research (ESDR)
  • Place of Presentation: Technical University of Munich, Munich, Germany
  • Year and Date: 2016-09-07 – 2016-09-10
  • Int'l Joint Research
• [Presentation] A role of spinal glial cells in pruritus of atopic dermatitis model mouse. (2016)
  • Author(s): Tominaga M, Torigoe K, Ogawa H, Takamori K.
  • Organizer: 46th Annual Meeting of the European Society for Dermatological Research (ESDR)
  • Place of Presentation: Technical University of Munich, Munich, Germany
  • Year and Date: 2016-09-07 – 2016-09-10
  • Int'l Joint Research
• [Presentation] Studies on a novel biomarker for atopic dermatitis. (2016)
  • Author(s): Iizumi K, Kawasaki H, Tominaga M, Shigenaga A, Kamo A, Kamata Y, Takamori K, Yamakura F.
  • Organizer: 16th IUBMB CONFERENCE
  • Place of Presentation: Vancouver Convention Center, Canada
  • Year and Date: 2016-07-17 – 2016-07-21
  • Int'l Joint Research
• [Book] Atopic dermatitis: Pruritus Second Edition. (2016)
  • Author(s): Tominaga M, Takamori K.
  • Total Pages: 453
  • Publisher: Springer Science+Business Media
• [Book] Itch in atopic dermatitis management. Curr Probl Dermatol. (2016)
  • Author(s): Kamata Y, Tominaga M, Takamori K
  • Total Pages: 209
  • Publisher: Karger
• [Remarks] 順天堂大学大学院医学研究科環境医学研究所 高森建二グループ
  • URL: http://www.juntendo.ac.jp/graduate/laboratory/labo/kankyo_igaku/k4_takamori.html
• [Remarks] Juntendo University, Itch Research Group
  • URL: http://www.juntendo.ac.jp/english/department/gra/gender_specific_medicine/takamori.html
• [Patent(Industrial Property Rights)] 掻痒性皮膚疾患の予防又は治療薬 (2017)
  • Inventor(s): 8. 楠部史也、冨永光俊、高森建二
  • Industrial Property Rights Holder: 8. 楠部史也、冨永光俊、高森建二
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 特願2017-028908号
  • Filing Date: 2017-02-20
• [Patent(Industrial Property Rights)] セマフォリン3A発現亢進剤 (2016)
  • Inventor(s): 五十嵐靖之、臼杵靖剛、田村具博、高森建二、他
  • Industrial Property Rights Holder: 五十嵐靖之、臼杵靖剛、田村具博、高森建二、他
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 特願2016-091429号
  • Filing Date: 2016-04-28