脂質輸送蛋白ＡＢＣＡ１２をターゲットとした、魚鱗癬各病型に対する新規治療法の開発

2013 Fiscal Year Annual Research Report

• Project/Area Number: 23249058
• Research Institution: Nagoya University
• Principal Investigator: 秋山 真志 名古屋大学, 医学(系)研究科(研究院), 教授 (60222551)
• Co-Investigator(Kenkyū-buntansha): 小川 靖 名古屋大学, 医学部附属病院, 病院助教 (10567754) ; 河野 通浩 名古屋大学, 医学(系)研究科(研究院), 講師 (60319324) ; 阿部 理一郎 北海道大学, 医学(系)研究科(研究院), 准教授 (60344511) ; 杉浦 一充 名古屋大学, 医学(系)研究科(研究院), 准教授 (70335032) ; 室 慶直 名古屋大学, 医学(系)研究科(研究院), 准教授 (80270990)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Keywords: 皮膚病理学 / 角化異常症

Research Abstract

１．先天性魚鱗癬様紅皮症を対象としたABCA12発現増強因子による治療戦略の開発
(1) ABCA12遺伝子変異を持つ、先天性魚鱗癬様紅皮症モデルマウスを作成し、そのモデルマウス由来培養表皮細胞を用いたABCA12発現増強因子の解析を行った。(2) ABCA12の発現増強効果が認められた薬剤につき、先天性魚鱗癬様紅皮症モデルマウス、および、患者由来表皮培養細胞に対する治療実験を施行し、ABCA12遺伝子および蛋白の発現をモニターし、ABCA12の発現増強効果、および、臨床症状の改善度を評価した。
２．魚鱗癬モデルマウスを対象としたABCA12発現増強因子による治療効果の評価
魚鱗癬モデルマウス個体に、ABCA12発現増強因子を投与し、皮膚表現型の改善を臨床的に評価した。また、角質水分量、経表皮的水分蒸散量など、皮膚のバリア機能の改善度を客観的に評価した。
３．道化師様魚鱗癬を対象としたリードスルー薬剤による治療効果の評価
(1) ABCA12変異を有する道化師様魚鱗癬モデルマウスの作成：日本人道化師様魚鱗癬同様に、ABCA12の機能喪失変異を有する道化師様魚鱗癬モデルマウスを作成した。(2) 上記１で作成したモデルマウスでのリードスルー治療実験： ABCA12変異に対するリードスルー活性が期待できる各種のリードスルー候補薬剤を種々の濃度で投与し、ABCA12の発現の回復をモニターし、表現形の改善を評価した。

Current Status of Research Progress

Reason

25年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

25年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Generalized pusular psoriasis triggered by amoxicillin in monozygotic twins with compound heterozygous IL36RN mutations: Comment on the article by Navarini et al. (2014)
  • Author(s): Sugiura K, Shoda Y, Akiyama M.
  • Journal Title: J Invest Dermatol Volume: 134 Pages: 578-579
  • DOI: doi: 10.1038/jid.2013.354.
  • Peer Reviewed
• [Journal Article] High survival rate of harlequin ichthyosis in Japan. (2014)
  • Author(s): Shibata A, Ogawa Y, Sugiura K, Muro Y, Abe R, Suzuki T, Akiyama M.
  • Journal Title: J Am Acad Dermatol Volume: 70 Pages: 387-388
  • DOI: doi: 10.1016/j.jaad.2013.10.055.
  • Peer Reviewed
• [Journal Article] Nuclear envelope localization of Ran-binding-protein 2 and Ran-GTPase-activating protein 1 in psoriatic epidermal keratinocytes. (2014)
  • Author(s): Yasuda K, Sugiura K, Takeichi T, Ogawa Y, Muro Y, Akiyama M.
  • Journal Title: Exp Dermatol Volume: 23 Pages: 119-124
  • DOI: doi: 10.1111/exd.12324.
  • Peer Reviewed
• [Journal Article] Highly prevalent LIPH founder mutations causing autosomal recessive woolly hair/hypotrichosis in Japan and the genotype/phenotype correlations. (2014)
  • Author(s): Tanahashi K, Sugiura K, Kono M, Takama H, Hamajima N, Akiyama M.
  • Journal Title: PLoS ONE Volume: 9 Pages: e89261
  • DOI: doi: 10.1371/journal.pone.0089261.
  • Peer Reviewed
• [Journal Article] Six-year-old boy with palmoplantar keratoderma with ichthyosis. (2014)
  • Author(s): Sugiura K, Oiso N, Kawada A, Akiyama M.
  • Journal Title: J Am Acad Dermatol Volume: 70 Pages: e51-52
  • DOI: doi: 10.1016/j.jaad.2013.08.054.
  • Peer Reviewed
• [Journal Article] The roles of ABCA12 in epidermal lipid barrier formation and keratinocyte differentiation. (2014)
  • Author(s): Akiyama M.
  • Journal Title: BBA-Mol Cell Biol L Volume: 1841 Pages: 435-440
  • DOI: doi: 10.1016/j.bbalip.2013.08.009.
  • Peer Reviewed
• [Journal Article] Prevalent founder mutation c.736T>A of LIPH in autosomal recessive woolly hair of Japanese leads to variable severity of hypotrichosis in adulthood. (2013)
  • Author(s): Tanahashi K, Sugiura K, Takeichi T, Takama H, Shinkuma S, Shimizu H, Akiyama M.
  • Journal Title: J Eur Acad Dermatol Venereol Volume: 27 Pages: 1182-1184
  • DOI: doi: 10.1111/j.1468-3083.2012.04526.x.
  • Peer Reviewed
• [Journal Article] Sporadic VACTERL association in a Japanese family with Sjogren-Larsson syndrome. (2013)
  • Author(s): Takeichi T, Sugiura K, Arai H, Ishii K, Kono M, Akiyama M.
  • Journal Title: Acta Dermato-Venereol Volume: 93 Pages: 579-580
  • DOI: doi: 10.2340/00015555-1526.
  • Peer Reviewed
• [Journal Article] A novel ATP2C1 early truncation mutation suggests haploinsufficiency as a pathogenic mechanism in a patient with Hailey-Hailey disease. (2013)
  • Author(s): Shibata A, Sugiura K, Kimura U, Takamori K, Akiyama M.
  • Journal Title: Acta Dermato-Venereol Volume: 93 Pages: 719-720
  • DOI: doi: 10.2340/00015555-1551.
  • Peer Reviewed
• [Journal Article] Novel ABCA12 missense mutation p.Phe2144Ser underlies congenital ichthyosiform erythroderma. (2013)
  • Author(s): Shimizu Y, Sugiura K, Aoyama Y, Ogawa Y, Hitomi K, Iwatsuki K, Akiyama M.
  • Journal Title: J Dermatol Volume: 40 Pages: 581-582
  • DOI: doi: 10.1111/1346-8138.12169.
  • Peer Reviewed
• [Journal Article] Clouston syndrome with heterozygous GJB6 mutation p.Ala88Val and GJB2 variant p.Val27Ile revealing mild sensorineural hearing loss and photophobia. (2013)
  • Author(s): Sugiura K, Teranishi M, Matsumoto Y, Akiyama M.
  • Journal Title: JAMA Dermatol Volume: 149 Pages: 1350-1351
  • DOI: doi: 10.1001/jamadermatol.2013.4766.
  • Peer Reviewed
• [Journal Article] Possible roles of barrier-to-autointegration factor 1 in regulation of keratinocyte differentiation and proliferation. (2013)
  • Author(s): Takama H, Sugiura K, Ogawa Y, Muro Y, Akiyama M.
  • Journal Title: J Dermatol Sci Volume: 71 Pages: 100-106
  • DOI: doi: 10.1016/j.jdermsci.2013.04.007.
  • Peer Reviewed
• [Journal Article] The majority of generalized pusular psoriasis without psoriasis vulgaris is caused by deficiency of interleukin-36 receptor antagonist. (2013)
  • Author(s): Sugiura K, Takemoto A, Yamaguchi M, Takahashi H, Shoda Y, Mitsuma T, Tsuda K, Nishida E, Togawa Y, Nakajima K, Sakakibara A, Kawachi S, Shimizu M, Ito Y, Takeichi T, Kono M, Ogawa Y, Muro Y, Ishida-Yamamoto A, Sano S, Matsue H, Morita A, Mizutani H, Iizuka H, Muto M, Akiyama M.
  • Journal Title: J Invest Dermatol Volume: 133 Pages: 2514-2521
  • DOI: doi: 10.1038/jid.2013.230.
  • Peer Reviewed
• [Journal Article] Impaired epidermal permeability barrier in mice lacking the Elovl1 gene responsible for very long-chain fatty acid production. (2013)
  • Author(s): Sassa T, Ohno Y, Suzuki S, Nomura T, Nishioka C, Kashiwagi T, Hirayama T, Akiyama M, Taguchi R, Shimizu H, Itohara S, Kihara A.
  • Journal Title: Mol Cell Biol Volume: 33 Pages: 2787-2796
  • DOI: doi: 10.1128/MCB.00192-13.
  • Peer Reviewed
• [Journal Article] Whole-exome sequencing identifies ADAM10 mutations as a cause of reticulate acropigmentation of Kitamura, a clinical entity distinct from Dowling-Degos disease. (2013)
  • Author(s): Kono M, Sugiura K, Suganuma M, Hayashi M, Takama H, Suzuki T, Matsunaga K, Tomita Y, Akiyama M.
  • Journal Title: Hum Mol Genet Volume: 22 Pages: 3524-3533
  • DOI: doi: 10.1093/hmg/ddt207.
  • Peer Reviewed
• [Journal Article] Aberrant distribution patterns of corneodesmosomal components of tape-stripped corneocytes in atopic dermatitis and related skin conditions (ichthyosis vulgaris, Netherton syndrome and peeling skin syndrome type B). (2013)
  • Author(s): Igawa S, Kishibe M, Honma M, Murakami M, Mizuno Y, Suga Y, Seishima M, Ohguchi Y, Akiyama M, Hirose K, Ishida-Yamamoto A, Iizuka H.
  • Journal Title: J Dermatol Sci Volume: 72 Pages: 54-60
  • DOI: doi: 10.1016/j.jdermsci.2013.05.004.
  • Peer Reviewed
• [Journal Article] Lamellar ichthyosis in a collodion baby caused by CYP4F22 mutations in a non-consanguineous family outside the Mediterranean. (2013)
  • Author(s): Sugiura K, Takeichi T, Tanahashi K, Ito Y, Kosho T, Saida K, Uhara H, Okuyama R, Akiyama M.
  • Journal Title: J Dermatol Sci Volume: 72 Pages: 193-195
  • DOI: doi: 10.1016/j.jdermsci.2013.06.008.
  • Peer Reviewed
• [Journal Article] Very mild lamellar ichthyosis with compound heterozygous TGM1 mutations including the novel missense mutation p.Leu693Phe. (2013)
  • Author(s): Sugiura K, Suga Y, Akiyama M.
  • Journal Title: J Dermatol Sci Volume: 72 Pages: 197-199
  • DOI: doi: 10.1016/j.jdermsci.2013.06.013.
  • Peer Reviewed
• [Journal Article] The novel CTSC homozygous nonsense mutation p.Lys106X in a patient with Papillon-Lefevre syndrome with all permanent teeth remaining at over 40 years of age. (2013)
  • Author(s): Kobayashi T, Sugiura K, Takeichi T, Akiyama M.
  • Journal Title: Br J Dermatol Volume: 169 Pages: 948-950
  • DOI: doi: 10.1111/bjd.12429.
  • Peer Reviewed
• [Presentation] 表皮細胞の分化に対する脂肪滴の影響、シンポジウム「脂肪滴研究の新たな展開：その多彩な機能と疾患」
  • Author(s): 秋山真志
  • Organizer: 第86回 日本生化学会大会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Invited