乾癬において発現異常を示す遺伝子群の病態形成に及ぼす重要性と質的な評価の研究

• Project/Area Number: 16790651
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Dermatology
• Research Institution: Fukushima Medical University
• Principal Investigator: 尾山 徳孝 福島県立医科大学, 医学部, 研究員 (30332927)
• Project Period (FY): 2004 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥3,400,000 (Direct Cost: ¥3,400,000); Fiscal Year 2006: ¥900,000 (Direct Cost: ¥900,000); Fiscal Year 2005: ¥1,200,000 (Direct Cost: ¥1,200,000); Fiscal Year 2004: ¥1,300,000 (Direct Cost: ¥1,300,000)
• Keywords: 乾癬 / プロモーター / 遺伝子 / DNAメチル化 / ゲノム / 医療・福祉 / 生体分子 / 発生・分化

Research Abstract

すでに我々はEGFR遺伝子の詳細な解析により、その転写調節領域(プロモーター)に乾癬患者特異的なDNAメチル化の異常を同定している。この領域のメチル化は転写因子AP-2の親和性を変化させることにより、EGFR発現調節を制御していることも報告した。これらの結果は、我々がin vitroで検討した乾癬ケラチノサイトにおけるEGFR発現異常のメカニズムを遺伝子レベルで支持するものであった。
平成17〜18年度にかけて、上記で同定された遺伝子群のメチル化異常が、実際に個々の遺伝子発現に及ぼす影響を検討してきた。メチル化依存的に生じる転写活性の違いを遺伝子ごとに測定し、これらを遺伝子間で比較することにより、乾癬の皮疹形成や臨床像の違いに関わる遺伝子の重要性の位置付けを試みた。その結果、EGFRのみならず乾癬で発現異常が報告されている他の遺伝子群の幾つかは、そのプロモーター領域でのメチル化異常を来たしている可能性が高いことが分かった。
今後はメチル化の違いによる疾患標的遺伝子の更なる絞込み、患者の家系内で検討、ならびに患者自身と一致したDNAメチル化パターンの遺伝性の有無や浸透性について検索すると同時に、個々の異常メチル化遺伝子、および特定のプロモーター部位を標的にした迅速、かつ簡便なin vitroでのメチル化同定方法の確立を試みる。

Research Products

• [Journal Article] Possible Involvement of Exon 31 Alternative Splicing in Phenotype and Severity of Epidermolysis Bullosa Caused by Mutations in PLEC1. (2007)
  • Author(s): Sawamura D, Goto M, Sakai K, Nakamura H, McMillan JR, Akiyama M, Shirado O, Oyama N, et al.
  • Journal Title: Journal of Investigative Dermatology (in press)
• [Journal Article] A case of localized dermatitis herpetiformis of the face : a literature review (2007)
  • Author(s): Kawakami Y, Oyama N, Nakamura K, Kaneko F
  • Journal Title: Journal of Americal Academy of Dermatology (in press)
• [Journal Article] Trichilemmal carcinoma arising in seborrheic keratosis : A case report and literature review (2007)
  • Author(s): Oyama N, Sakuma H, Kaneko F
  • Journal Title: British Journal of Dermatology (in press)
• [Journal Article] Bullous pemphigoid antigen II(BP180)and its soluble extracellular domains are major autoantigens in mucous membrane pemphigoid : the pathogenic relevance to HLA class II alleles and disease severity (2006)
  • Author(s): Oyama N et al.
  • Journal Title: British Journal of Dernatology 154 Pages: 90-98
• [Journal Article] Role of IL12B promoter polymorphism in Behcet's disease susceptibility : an involvement of Th1 immunoreactivity against Streptococcus Sanguinis antigen (2006)
  • Author(s): Yanagihori H, Oyama N et al.
  • Journal Title: J Invest Dermatol 2(in press)
• [Journal Article] Extracellular matrix protein 1 inhibits the activity of matrix metalloproteinase 9 through high-affinity protein/protein interactions (2006)
  • Author(s): Fujimoto N, Terlizzi J, Aho S, Brittingham R, Fertala A, Oyama N et al.
  • Journal Title: Experimental Dermatology 15 Pages: 300-307
• [Journal Article] Usefulness of BP180 NC16a ELISA in the serodiagnosis of PG and in differentiating between PG and PUPPP (2005)
  • Author(s): Powell AM, Sakuma-Oyama Y, Oyama N et al.
  • Journal Title: Archives of Dermatology 141 Pages: 705-710
• [Journal Article] epidermolysis bullos Increased serum levels of IL-6, immunoglobulin and acute phase protein in patients with the severe clinical form of inherited a (2005)
  • Author(s): Kawakami Y, Oyama N et al.
  • Journal Title: Journal of Dermatology 32 Pages: 503-505
• [Journal Article] Collagen XVII/BP180: a collagenous transmembrane protein and component of the dermoepidermal anchoring complex (2005)
  • Author(s): Powell AM, Sakuma-Oyama Y, Oyama N et al.
  • Journal Title: atoloClinical & Experimental Dermgy 30 Pages: 682-687
• [Journal Article] Mannose-binding lectin(MBL)single nucleotide polymorphism is not associated with atopic dermatitis in Japanese patients (2005)
  • Author(s): Hashimoto S, Nakamura K, Oyama N et al.
  • Journal Title: Journal of Dermatology 32 Pages: 1038-1040
  • NAID: 10020272305
• [Journal Article] Recurrent mutations in kindlin-1, a novel keratinocyte focal contact protein, in the autosomal recessive skin fragility and photosensitivity disorder, Kindler syndrome. (2004)
  • Author(s): Ashton GHS, McLean WHI, South AP, Oyama N et al.
  • Journal Title: J Invest Dermatol 122 Pages: 78-83
• [Journal Article] A case of generalized pustular psoriasis associated with turner syndrome. (2004)
  • Author(s): Kawakami Y, Oyama N, Kishimoto K et al.
  • Journal Title: J Dermatol 31 Pages: 16-20
  • NAID: 10016258586
• [Journal Article] Paraneoplastic pemphigus secondary to fludarabine evolving into unusual oral pemphigus vegetans (2004)
  • Author(s): Powell AM, Albert S, Oyama N et al.
  • Journal Title: J Eur Acad Dermatol Venereol 12 Pages: 360-364
• [Journal Article] Enhanced TARC production by dust-mite allergens and its modulation by immunosuppressive drugs in PBMCs from patients with atopic dermatitis (2004)
  • Author(s): Furukawa H, Nakamura K, Zheng X, Tojo M, Oyama N et al.
  • Journal Title: J Dermatol Sci 35 Pages: 35-42
  • NAID: 10016184234
• [Journal Article] Bullous pemphigoid antigen II (BP180) and its soluble extracellular domains are major autoantigens in mucous membrane pemphigoid
  • Author(s): Oyama N et al.
  • Journal Title: Br J Dermatol (in press)
• [Journal Article] The c-kit mutations in patients with child-onset mastocytosis and its clinical correlation
  • Author(s): Yanagihori H, Oyama N et al.
  • Journal Title: J Mol Diag (in press)