皮膚疾患の病態におけるD-DTの機能解析と新規治療法開発への展開

• Project/Area Number: 21K08342
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53050:Dermatology-related
• Research Institution: University of Toyama
• Principal Investigator: 清水 忠道 富山大学, 学術研究部医学系, 教授 (70260396)
• Co-Investigator(Kenkyū-buntansha): 牧野 輝彦 富山大学, 学術研究部医学系, 准教授 (90359711)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Granted (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: D-dopachrome tautomerase / MIF / 炎症 / アトピー性皮膚炎 / 尋常性乾癬 / 強皮症 / allergy / eosinophil / cytokine / inflammation / D-DT / サイトカイン

Outline of Research at the Start

マクロファージ遊走阻止因子（MIF）の機能的ホモログであるD-dopachrome tautomerase（D-DT）が炎症性サイトカインとしての機能を有する可能性が報告された．D-DTはMIFと同様にCD74をその受容体にすることからも，MIFと類似した機能をもつと推察されているがD-DTの詳細な機能は未だ明らかではない．本研究では，炎症性疾患であるアトピー性皮膚炎，乾癬および自己免疫性疾患である強皮症の病態におけるD-DTの役割を各種疾患のマウスモデルと患者の臨床検体を用いて解析し，炎症性疾患および自己免疫疾患の治療法の開発を試みる.

Outline of Annual Research Achievements

D-dopachrome tautomerase(D-DT/MIF-2)は炎症性サイトカインの1つであるMacrophage migration inhibitory factor(MIF)の機能的相同体とされる。これまでの研究でD-DTはMIFと類似した機能を持つと推察されてきたが、その詳細は未だ明らかではない。MIFはアレルギー性疾患や炎症性疾患などに対して広く適応できる新規治療ターゲットと期待されており、機能的相同体であるD-DTも同様に重要な因子と推測される。D-DTは気管支や腸管上皮、表皮角化細胞などにも発現し、私共は光発癌の発症にも関連していることを明らかにした(FASEB J, 2021) 。MIFとの相同性から考えるにアレルギー性疾患、炎症や免疫応答への関与が想像できる。本研究では、アトピー性皮膚炎や尋常性乾癬、強皮症といった炎症性皮膚疾患発症メカニズムに対するD-DTの機能解析をD-DT 過剰発現（Tg）マウスを使って行っている。今年度はこれらの疾患への関与についてさらに深く検討を行うため、新たにD-DTノックアウト(KO)マウスを作製している。

Current Status of Research Progress

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

Reason

研究は当初の計画通りに進んでいる。

Strategy for Future Research Activity

アトピー性皮膚炎、乾癬および強皮症マウスモデルにD-DT TgマウスとD-DTノックアウトマウスを適用しこれらの疾患の病態におけるD-DTの関与をWTマウスと比較解析する。

Research Products

• [Journal Article] Non-canonical Regulation of EGFR by the Air Pollutant 9,10-Phenanthrenequinone (2022)
  • Author(s): Yamagishi N, Takahashi JI, Zhou Y, Yokoyama S, Makino T, Shimizu T, Sakurai H.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 45 Issue: 10 Pages: 1553-1558
  • DOI: 10.1248/bpb.b22-00489
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2022-10-01
  • Peer Reviewed
• [Journal Article] Adult T-cell leukemia/lymphoma showing parakeratosis variegate. (2022)
  • Author(s): Torai R, Makino T, Matsui Y, Shimizu T.
  • Journal Title: Int J Dermatol. Volume: 61(2) Issue: 2
  • DOI: 10.1111/ijd.15639
  • Peer Reviewed / Open Access
• [Journal Article] Newborn twins with neonatal pemphigoid gestationis. (2022)
  • Author(s): Kitayama S, Makino T, Mizawa M, Shimizu T.
  • Journal Title: J Dermatol. Volume: 49(5) Issue: 5
  • DOI: 10.1111/1346-8138.16291
  • Peer Reviewed
• [Journal Article] SuSuccessful treatment with excimer laser for cutaneous lesion of sarcoidosis. (2022)
  • Author(s): Makino T, Kataoka K, Kitayama S, Mizawa M, Shimizu T
  • Journal Title: J Dermatol. Volume: 49(7) Issue: 7
  • DOI: 10.1111/1346-8138.16357
  • Peer Reviewed
• [Journal Article] Efficacy of Q-switched ruby laser treatment for pigmented fungiform papillae of the tongue. (2022)
  • Author(s): Mizawa M, Makino T, Furukawa F, Torai R, Shimizu T.
  • Journal Title: J Dermatol. Volume: 49(4) Issue: 4
  • DOI: 10.1111/1346-8138.16270
  • Peer Reviewed
• [Journal Article] Cutaneous gnathostomiasis caused by Gnathostoma spinigerum. (2022)
  • Author(s): Makino T, Sugiyama H, Oshima M, Mizawa M, Shimizu T.
  • Journal Title: Br J Dermatol. Volume: 186(5) Issue: 5
  • DOI: 10.1111/bjd.21007
  • Peer Reviewed
• [Journal Article] A case of linear IgA disease with IgA antibodies to type VII collagen demonstrated by immunofluorescence overlay antigen mapping (2022)
  • Author(s): Kitayama S, Makino T, Hayashi M, Furukawa F, Torai R, Mizawa M, Ishii N, Hashimoto T, Shimizu T.
  • Journal Title: Eur J Dermatol. Volume: 32 Issue: 4 Pages: 553-554
  • DOI: 10.1684/ejd.2022.4312
  • Peer Reviewed
• [Journal Article] Identification of a de novo mutation of the elastin gene by targeted exome sequencing in autosomal dominant cutis laxa (2022)
  • Author(s): Makino T, Terada Y, Mizawa M, Hirono K, Adachi Y, Aoki S, Kubo A, Shimizu T.
  • Journal Title: Clin Exp Dermatol Volume: 47 Issue: 10 Pages: 1895-1897
  • DOI: 10.1111/ced.15303
  • Peer Reviewed
• [Journal Article] Berberine induces anti-atopic dermatitis effects through the downregulation of cutaneous EIF3F and MALT1 in NC/Nga mice with atopy-like dermatitis. (2021)
  • Author(s): Andoh T, Yoshihisa Y, Rehman MU, Tabuchi Y, Shimizu T
  • Journal Title: Biochem Pharmacol Volume: 185 Pages: 114439-114439
  • DOI: 10.1016/j.bcp.2021.114439
  • Peer Reviewed / Open Access
• [Journal Article] Overexpression of D-dopachrome tautomerase increases ultraviolet B irradiation-induced skin tumorigenesis in mice (2021)
  • Author(s): Yoshihisa Y, Rehman MU, Andoh T, Tabuchi Y, Makino T, Shimizu T
  • Journal Title: FASEB J Volume: 35 Issue: 7
  • DOI: 10.1096/fj.202002631rrr
  • Peer Reviewed / Open Access
• [Journal Article] Dysregulation of Amphiregulin stimulates the pathogenesis of cystic lymphangioma (2021)
  • Author(s): Yoshida N, Yamamoto S, Hamashima T, Okuno N, Okita N, Horikawa S, Hayashi M, Dang TC, Nguyen QL, Nishiyama K, Makino T, Ishii Y, Tomihara K, Shimizu T, Shibuya M, Noguchi M, Sasahara M.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 118 Issue: 19
  • DOI: 10.1073/pnas.2019580118
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association of Development of Solar Elastosis with Increased Expression of Fibrillin-1, LTBP-2 and Fibulin-4 in Combination with Decreased Expression of LTBP-4 (2021)
  • Author(s): Makino T、Kagoyama K、Murabe C、Nakamura T、Shimizu T
  • Journal Title: Acta Dermato Venereologica Volume: 101 Issue: 1 Pages: adv00372-adv00372
  • DOI: 10.2340/00015555-3738
  • Peer Reviewed / Open Access
• [Journal Article] Expression of laminin-5 gamma 2 chain predicts invasion of extramammary Paget's disease cell. (2021)
  • Author(s): Tohmatsu Y, Imura J, Sakai T, Takagi K, Minamisaka T, Tanaka S, Noguchi A, Nakajima T, Nagata T, Makino T, Shimizu T, Fujii T.
  • Journal Title: APMIS. Volume: 129 Issue: 1 Pages: 3-8
  • DOI: 10.1111/apm.13086
  • Peer Reviewed / Open Access
• [Presentation] D-dopachrome tautomerase overexpression accelerates photocarcinogenesis in mice. (2022)
  • Author(s): Shimizu T, Andoh T, Yoshihisa Y, Makino T.
  • Organizer: 80th Society for Investigative Dermatology(SID) Annual Meeting
  • Int'l Joint Research
• [Presentation] Two cases of granuloma annulare successfully treated with excimer laser. (2022)
  • Author(s): Mizawa M, Makino T, Oshima M, Hayashi M, Shimizu T.
  • Organizer: The 12th Asian Dermatological Congress(ADC)
  • Int'l Joint Research
• [Presentation] Kampo medicine in the field of dermatology: basic clinical aspects.“1st International Symposium on Kampo Medicine”. (2022)
  • Author(s): Andoh T, Shimizu T, Toyoda M, Maeda M.
  • Organizer: 1st International Symposium on Kampo Medicine
  • Int'l Joint Research
• [Presentation] Expression of S100-fused proteins in a three-dimensional atopic dermatitis skin. (2022)
  • Author(s): Makino T, Yamamoto S, Takemoto K, Mizawa M, Shimizu T.
  • Organizer: The 47th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Int'l Joint Research
• [Presentation] 光老化のアップデート. (2022)
  • Author(s): 清水忠道.
  • Organizer: 第121回日本皮膚科学会総会
  • Invited
• [Presentation] Association of Development of Solar Elastosis with Increased Expression of Fibrillin-1,LTBP-2 and Fibulin-4 in Combination with Decreased Expression of LTBP-4. (2021)
  • Author(s): Makino T, Kagoyama K, Murabe C, Nakamura T, Shimizu T.
  • Organizer: 79th Society for Investigative Dermatology(SID) Annual Meeting
  • Int'l Joint Research
• [Presentation] A role of elastogenic factors in the pathogenesis of solar elastosis. (2021)
  • Author(s): Makino T, Kagoyama K, Murabe C, Nakamura T, Shimizu T.
  • Organizer: The 46th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Int'l Joint Research
• [Presentation] Genipin contained in gardenia fruit enhanced melanogenesis. (2021)
  • Author(s): Mizawa M, Andoh T, Shimizu T.
  • Organizer: The 46th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Int'l Joint Research
• [Presentation] サイトカインと光医学研究-私の歩んできた道-. (2021)
  • Author(s): 清水忠道
  • Organizer: 第42回日本光医学・光生物学会
  • Invited
• [Presentation] リンパ節生検における超音波検査の有用性. (2021)
  • Author(s): 鹿児山浩, 寺田義之, 竹本景太, 虎井僚太郎, 牧野輝彦, 清水忠道.
  • Organizer: 第36回日本皮膚外科学会総会学術集会・第39回日本臨床皮膚外科学会総会学術大会・The 6th Asian Congress of Dermatologic Surgery(3学会合同開催）
• [Book] 今日の皮膚疾患治療指針 第5版. (2022)
  • Author(s): 清水忠道.
  • Total Pages: 4
  • Publisher: 医学書院
  • ISBN: 9784260045933
• [Book] 目で見て役立つ薬疹の上手な診かた・対応ガイド. (2022)
  • Author(s): 三澤 恵, 清水忠道.
  • Total Pages: 5
  • Publisher: 診断と治療社
  • ISBN: 9784787880314
• [Book] 今日の治療指針 2021年版(Vol.63).（分担：光線過敏症） (2021)
  • Author(s): 清水忠道.
  • Total Pages: 1
  • Publisher: 医学書院
  • ISBN: 9784260042826
• [Book] 皮膚疾患最新の治療 2021-2022.（分担：伝染性軟属腫） (2021)
  • Author(s): 清水忠道.
  • Total Pages: 1
  • Publisher: 南江堂
  • ISBN: 9784524227990
• [Remarks] 富山大学医学部皮膚科学講座研究業績
  • URL: http://www.med.u-toyama.ac.jp/derma2/study/#kenkyu