ダブルノックアウトマウスを利用したアトピー性皮膚炎モデルマウスの作製

2013 年度 研究成果報告書

• 研究課題/領域番号: 22591240
• 研究種目: 基盤研究(C)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 皮膚科学
• 研究機関: 香川大学
• 研究代表者: 米田 耕造 香川大学, 医学部附属病院, 准教授 (60260626)
• 研究分担者: 窪田 泰夫 香川大学, 医学部, 教授 (10126047) ; 荒木 伸一 香川大学, 医学部, 教授 (10202748) ; 中井 浩三 香川大学, 医学部, 助教 (40363204)
• 研究期間 (年度): 2010-04-01 – 2014-03-31
• キーワード: ロリクリン / ノックアウトマウス / 魚鱗癬 / アトピー性皮膚炎

研究概要

アトピー性皮膚炎は、掻痒の強い湿疹病変を主とする難治性皮膚疾患であり、フィラグリンタンパク質の遺伝子異常による。ロリクリンはフィラグリンと同様、表皮角層細胞の辺縁帯の主成分である。ロリクリン遺伝子の変異による疾患（亜型ボーウィンケル症候群）の臨床症状は、掌蹠角化症を合併した魚鱗癬であり、フィラグリン遺伝子機能喪失変異により生じる尋常性魚鱗癬の臨床症状に酷似している。本研究の目的は、アトピー性皮膚炎の動物モデルを作製し、その病態に関与するロリクリンの果たす役割を解析し、創薬に役立てることである。その目的に向けてわれわれはロリクリンノックアウトマウスを作製した。

研究成果

• [雑誌論文] Detection of apoptotic keratinocytes in a case of bullous pemphigoid developed after graft-versus-host disease (2014)
  • 著者名/発表者名: Yoneda K, Demitsu T, Kakurai M, Narita T, Nakai K, Kubota Y, Ishii N and Hashimoto T
  • 雑誌名: Acta Derm Venereol 巻: 94 ページ: 231-232
• [雑誌論文] Multi-branched acquired periungual fibrokeratoma (2014)
  • 著者名/発表者名: Moriue T, Yoneda K, Moriue J, Nakai K and Kubota Y
  • 雑誌名: JAMA Dermatol 巻: (Epub ahead of print)
  • DOI: 10.1001/jamadermatol.2013.6631
• [雑誌論文] Two cases of nevus sebaceous accompanying secondary tumors with Klothov expression (2014)
  • 著者名/発表者名: Nakai K, Yoneda K, Haba R, Kushida Y, Katsuki N, Moriue J, Moriue T, Ishikawa E, Inoue S and Kubota Y
  • 雑誌名: J Dermatol 巻: 41 ページ: 171-172
  • DOI: 10.1111/1346-8138.12371
• [雑誌論文] A survey of the factors associated with concerns about oral antihistamine use in Japanese pruritic 30. Hosokawa Y, Yoneda K, Nakai K, Moriue J and Kubota Y: Completely thrombosed venous aneurysm in great saphenous vein (2013)
  • 著者名/発表者名: Moriue J, Yoneda K, Nakai K, Hosokawa Y, Moriue T, and Kubota Y
  • 雑誌名: Ann Dermatol 巻: 25 ページ: 268-270
• [雑誌論文] Paraneoplastic pemphigus mimicking toxic epidermal necrolysis associated with B-cell lymphoma (2013)
  • 著者名/発表者名: Yamada T, Nakamura S, Demitsu T, Nakamura T, Iida E, Yoneda K, Fukuda S and Hashimoto T
  • 雑誌名: J Dermatol 巻: 40 ページ: 286-288
• [雑誌論文] Dexamethasone induces caveolin-1 in vascular endothelial cells: implications for attenuated responses to VEGF (2013)
  • 著者名/発表者名: Igarashi J, Hashimoto T, Shoji K, Yoneda K, Tsukamoto I, Moriue T, Kubota Y and Kosaka H
  • 雑誌名: Am J Physiol Cell Physiol 巻: 304 ページ: C790-800
• [雑誌論文] Sphingosine 1-phosphate attenuates peroxide-induced apoptosis in HaCaT cells cultured in vitro (2013)
  • 著者名/発表者名: Moriue T, Igarashi J, Yoneda K, Hashimoto T, Nakai K, Kosaka H and Kubota Y
  • 雑誌名: Clin Exp Dermatol 巻: 38 ページ: 638-645
• [雑誌論文] Primary dermal melanoma latent for more than 10 years (2013)
  • 著者名/発表者名: Moriue J, Yoneda K, Moriue T, Nakai K, Katsuki N, Haba R, Ikeda M and Kubota Y
  • 雑誌名: Ann Dermatol 巻: 25 ページ: 385-386
• [雑誌論文] Successful treatment of primary cutenous anaplastic large cell lymphoma with intralesional methotrexate therapy (2013)
  • 著者名/発表者名: Yokoi I, Ishikawa E, Koura A, Hosokawa Y, Tamai A, Nakai K, Moriue J, Moriue T, Yoneda K and Kubota Y
  • 雑誌名: Acta Derm Venereol 巻: (Epub ahead of print)
  • DOI: 10.2340/00015555-1692
• [雑誌論文] Deranged epidermal differentiation in kl/kl mouse and the effects of Klotho siRNA on the differentiation of HaCaT cells (2013)
  • 著者名/発表者名: Nakai K, Yoneda K, Haba R, Kushida Y, Katsuki N, Moriue T, Kosaka H, Kubota Y and Inoue S
  • 雑誌名: Exp Dermatol 巻: (Epub ahead of print)
  • DOI: 10.1111/exd.12258
• [雑誌論文] Combination effects of cosmetic moisturisers in the topical treatment of acne vulgaris (2012)
  • 著者名/発表者名: Munehiro A, Murakami Y, Shirahige Y, Nakai K, Moriue T, Matsunaka H, Yoneda K and Kubota Y
  • 雑誌名: J Dermatol Treat 巻: 23 ページ: 172-176
• [雑誌論文] A case of Degos disease successfully treated with corticosteroid combined with cyclophosphamide (2012)
  • 著者名/発表者名: Kameda T, Dobashi H, Yoneda K, Susaki K, Kuno T, Murao K and Ishida T
  • 雑誌名: Rheumatol Int 巻: 32 ページ: 2169-2173
• [雑誌論文] Scedosporium apiospermum skin infection mimicking tuberous xanthoma (2012)
  • 著者名/発表者名: Yoneda K, Nakai K, Moriue T, Ishikawa E, Demitsu T, Ohkusu K and Kubota Y
  • 雑誌名: J Dermatol 巻: 39 ページ: 316-318
• [雑誌論文] Numerous mucin nodules in a patient with seropositive wide spread discoid lupus erythematosus (2012)
  • 著者名/発表者名: Yoneda K, Moriue J, Nakai K, Demitsu T, Moriue T, Yokoi I, Munehiro A, Dobashi H and Kubota Y
  • 雑誌名: Ann Dermatol 巻: 24 ページ: 112-114
• [雑誌論文] The profilaggrin N-terminal domain is absent in pityriasis rotunda (2012)
  • 著者名/発表者名: Yoneda K, Presland RB, Demitsu T, Shimizu T and Kubota Y
  • 雑誌名: Br J Dermatol 巻: 166 ページ: 227-229
• [雑誌論文] Juvenile xanthogranuloma with lichenoid appearance (2012)
  • 著者名/発表者名: Yoneda K, Demitsu T and Kubota Y
  • 雑誌名: J Dermatol 巻: 39 ページ: 462-465
• [雑誌論文] Interaction of the profilaggrin N-terminal domain with loricrin in human cultured keratinocytes and epidermis (2012)
  • 著者名/発表者名: Yoneda K, Nakagawa T, Lawrence OT, Huard J, Demitsu T, Kubota Y and Presland RB
  • 雑誌名: J Invest Dermatol 巻: 132 ページ: 1206-1214
• [雑誌論文] Effect of sequential application of topical adapalene and clindamycin phosphate in the treatment of Japanese patients with acne vulgaris (2012)
  • 著者名/発表者名: Kubota Y, Munehiro A, Shirahige Y, Nakai K, Katsuura J, Moriue T, Murakami Y, Matsunaka H and Yoneda K
  • 雑誌名: J Dermatol Treat 巻: 23 ページ: 37-45
• [雑誌論文] Inflammatory disseminated superficial porokeratosis with an unusual clinical feature of the pruritic, erythematous papules preceding annular brownish pigmentation (2012)
  • 著者名/発表者名: Wakatabi K, Kakurai M, Yamada T, Umemoto N, Demitsu T and Yoneda K
  • 雑誌名: J Dermatol 巻: 39 ページ: 946-948
• [雑誌論文] Cutaneous Mycobacterium marinum infection mimicking felon in a patient with psoriatic arthritis treated with infliximab (2012)
  • 著者名/発表者名: Demitsu T, Yamada T, Umemoto N, Narita T, Kakurai M and Yoneda K
  • 雑誌名: J Dermatol 巻: 39 ページ: 970-971
• [雑誌論文] Primary cutaneous cryptococcosis in a patient with CREST syndrome (2012)
  • 著者名/発表者名: Ishikawa E, Yoneda K, Nakai K, Moriue J, Yokoi I, Munehiro A and Kubota Y
  • 雑誌名: Eur J Dermatol 巻: 22 ページ: 421-422
• [雑誌論文] Macular lymphocytic arteritis in a patient with rheumatoid arthritis (2012)
  • 著者名/発表者名: Munehiro A, Yoneda K, Koura A, Nakai K and Kubota Y
  • 雑誌名: Eur J Dermatol 巻: 22 ページ: 427-42
• [雑誌論文] Pinch and ligation method: a new non-surgical approach to viral warts (2012)
  • 著者名/発表者名: Moriue T, Yoneda K, Moriue J, Nakai K, Yokoi I, Fujita N, Munehiro A, Maeda R and Kubota Y
  • 雑誌名: J Dermatol 巻: 39 ページ: 1108-1109
• [雑誌論文] Pustular psoriasis precipitated by cytomegalovirus infection (2012)
  • 著者名/発表者名: Yoneda K, Matsuoka-Shirahige Y, Demitsu T and Kubota Y
  • 雑誌名: Br J Dermatol 巻: 167 ページ: 1186-1189
• [雑誌論文] Reduced expression of epidermal growth factor receptor, E-cadherin, and occludin in the skin of flaky tail mice is due to filaggrin and loricrin deficiencies (2012)
  • 著者名/発表者名: Nakai K, Yoneda K, Hosokawa Y, Moriue T, Presland RB, Fallon PG, Kabashima K, Kosaka H and Kubota Y
  • 雑誌名: Am J Pathol 巻: 181 ページ: 969-977
• [雑誌論文] A founder effect of c.1938delC in ITGB4 underlies junctional epidermolysis bullosa and its application for prenatal testing (2011)
  • 著者名/発表者名: Natsuga K, Nishie W, Shinkuma S, Nakamura H, Arita K, Yoneda K, Kusaka T, Yanagihara T, Kosaki R, Sago H, Akiyama M and Shimizu H
  • 雑誌名: Exp Dermatol 巻: 20 ページ: 74-76
• [雑誌論文] Lipid peroxidation-induced VEGF expression in the skin of KKAy obese mice (2011)
  • 著者名/発表者名: Nakai K, Yoneda K, Ishihara Y, Ohmori K, Moriue T, Igarashi J, Kohno M, Kosaka H and Kubota Y
  • 雑誌名: Exp Dermatol 巻: 20 ページ: 388-393
• [雑誌論文] Skin infiltration of pelvic actinomycosis after total gastrectomy (2011)
  • 著者名/発表者名: Yoneda K, Nakai K, Hosokawa Y, Moriue T, Demitsu T and Kubota Y
  • 雑誌名: Eur J Dermatol 巻: 21 ページ: 290-291
• [雑誌論文] Unilateral palm pompholyx in a patient with amyotrophic lateral sclerosis (2011)
  • 著者名/発表者名: Nakai K, Yoneda K, Moriue T, Hosokawa Y, Yokoi I and Kubota Y
  • 雑誌名: Eur J Dermatol 巻: 21 ページ: 445-446
• [雑誌論文] Sarcoidosis presenting transepidermal elimination (2011)
  • 著者名/発表者名: Yoneda K, Kakurai M, Umemoto N, Nakai K, Kubota Y and Demitsu T
  • 雑誌名: Eur J Dermatol 巻: 21 ページ: 616-617
• [雑誌論文] Consequences of two different amino-acid substitutions at the same codon in KRT14 indicate definitive roles of structural distortion in epidermolysis bullosa simplex pathogenesis (2011)
  • 著者名/発表者名: Natsuga K, Nishie W, Smith BJ, Shinkuma S, Smith TA, Parry DA, Oiso N, Kawada A, Yoneda K, Akiyama M and Shimizu H
  • 雑誌名: J Invest Dermatol 巻: 131 ページ: 1869-1876
• [雑誌論文] Activation of vascular endothelial growth factor receptor 2 in a cellular model of loricrin keratoderma (2010)
  • 著者名/発表者名: Yoneda K, Demitsu T, Nakai K, Moriue T, Ogawa W, Igarashi J, Kosaka H and Kubota Y
  • 雑誌名: J Biol Chem 巻: 285 ページ: 16184-16194
• [雑誌論文] Community-based epidemiological study of psychosocial effects of acne in Japanese adolescents (2010)
  • 著者名/発表者名: Kubota Y, Shirahige Y, Nakai K, Katsuura J, Moriue T and Yoneda K
  • 雑誌名: J Dermatol 巻: 37 ページ: 617-622
• [雑誌論文] Clinical efficacy of reserpine as "add-on therapy" to antihistamines in patients with recalcitrant chronic idiopathic urticaria and urticarial vasculitis (2010)
  • 著者名/発表者名: Demitsu T, Yoneda K, Kakurai M, Sasaki K, Hiratsuka Y, Azuma R, Yamada T and Umemoto N
  • 雑誌名: J Dermatol 巻: 37 ページ: 827-829
• [雑誌論文] Bevacizumab-induced hand-foot syndrome: circumscribed type (2010)
  • 著者名/発表者名: Munehiro A, Yoneda K, Nakai K, Demitsu T, Moriue T, Moriue J, Yokoi I, Fujita N, Matsuura N, Ishikawa S, Yokomise H and Kubota Y
  • 雑誌名: Br J Dermatol 巻: 162 ページ: 1411-1413
• [雑誌論文] Expression of wild-type, but not mutant, loricrin causes programmed cell death in HaCaT keratinocytes (2010)
  • 著者名/発表者名: Yoneda K, Demitsu T, Manabe M, Igarashi J, Kosaka H, Inagaki N, Takahashi H, Kon A, Kakurai M and Kubota Y
  • 雑誌名: J Dermatol 巻: 37 ページ: 956-964
• [雑誌論文] Late radiation dermatitis of the right arm after cardiac catheterization (2010)
  • 著者名/発表者名: Yoneda K, Nakai K, Demitsu T, Moriue T, Moriue J, Yokoi I, Munehiro A, Noma T, Kohno M and Kubota Y
  • 雑誌名: Eur J Dermatol 巻: 20 ページ: 654-656
• [雑誌論文] Seborrhoeic keratoses and acanthosis nigricans in a long-term survivor of thanatophoric dysplasia (2010)
  • 著者名/発表者名: Nakai K, Yoneda K, Moriue T, Munehiro A, Fujita N, Moriue J, Yokoi I, Haba R, Itoh S and Kubota Y
  • 雑誌名: Br J Dermatol 巻: 163 ページ: 656-658
• [雑誌論文] Zosteriform cutaneous metastasis of lung adenocarcinoma
  • 著者名/発表者名: Kubota Y, Nakai K, Munehiro A, Moriue J and Yoneda K
  • 雑誌名: J Clin Exp Dermatol Res 巻: 36 (in press)
• [雑誌論文] Pachyonychia congenita in Japan: report of familial cases with a recurrent KRT16 mutation and review of the literature
  • 著者名/発表者名: Inaba Y, Kanazawa N, Furukawa F, Sakurane Y, Nakano H, Sawamura D, Yoneda K, Hamada T and Hashimoto T
  • 雑誌名: Eur J Dermatol 巻: (in press)
• [学会発表] Cytomegalovirus infection is one of the precipitating factors for pustular psoriasis (2012)
  • 著者名/発表者名: Yoneda K, Matsuoka-Shirahige Y, Demitsu T and Kubota Y
  • 学会等名: The 37^<th> Annual Meeting of the Japanese Society for Investigative Dermatology
  • 発表場所: Okinawa
  • 年月日: 2012-12-07
• [学会発表] Klotho regulates the differentiation and tumorgenesis of epidermal keratinocytes (2012)
  • 著者名/発表者名: Nakai K, Inoue S, Haba R, Kushida Y, Katsuki N, Hosokawa Y, Moriue T, Yoneda K and Kubota Y
  • 学会等名: The 37^<th> Annual Meeting of the Japanese Society for Investigative Dermatology
  • 発表場所: Okinawa
  • 年月日: 2012-12-07
• [学会発表] Reduced expression of EGF receptor, E-cadherin and occludin is due to loricrin deficiency in the skin of flaky tail mice (2011)
  • 著者名/発表者名: Nakai K, Yoneda K, Hosokawa Y, Moriue T and Kubota Y
  • 学会等名: The 36^<th> Annual Meeting of the Japanese Society for Investigative Dermatology
  • 発表場所: Kyoto
  • 年月日: 2011-12-09
• [学会発表] Direct effects of bevacizumab on cell proliferation and cell signaling pathways in HaCaT cells (2011)
  • 著者名/発表者名: Hosokawa Y, Yoneda K, Moriue T, Nakai K and Kubota Y
  • 学会等名: The 36^<th> Annual Meeting of the Japanese Society for Investigative Dermatology
  • 発表場所: Kyoto
  • 年月日: 2011-12-09
• [学会発表] The profilaggrin N-terminal domain is absent in pityriasis rotunda (2011)
  • 著者名/発表者名: Yoneda K, Presland RB, Demitsu T, Shimizu T and Kubota Y
  • 学会等名: The 36^<th> Annual Meeting of the Japanese Society for Investigative Dermatology
  • 発表場所: Kyoto
  • 年月日: 2011-12-09
• [学会発表] Abnormally aggregated caveolin-1 in the cytoplasm of cellular model of classic Vohwinkel syndrome (2010)
  • 著者名/発表者名: Yoneda K, Nakai K, Moriue T, Demitsu T and Kubota Y
  • 学会等名: The 35^<th> Annual Meeting of the Japanese Society for Investigative Dermatology
  • 発表場所: Wakayama
  • 年月日: 2010-12-04
• [学会発表] The effects of oxidized LDL on VEGF production in HaCaT cells: a possible mechanism for psoriasis in metablic syndrome (2010)
  • 著者名/発表者名: Nakai K, Yoneda K, Ishihara Y, Ohmori K, Moriue T, Igarashi J, Kohno M, Kosaka H and Kubota Y
  • 学会等名: The 35^<th> Annual Meeting of the Japanese Society for Investigative Dermatology
  • 発表場所: Wakayama
  • 年月日: 2010-12-03
• [学会発表] Pitavastatin suppresses lipid peroxidation-induced VEGF expression in the skin of KKAy metabolic syndrome mice (2010)
  • 著者名/発表者名: Nakai K, Yoneda K, Ishihara Y, Ohmori K, Moriue T, Igarashi J, Kohno M, Kosaka H and Kubota Y
  • 学会等名: 17^<th> Annual Meeting of The Society for Free Radical Biology and Medicine
  • 発表場所: Orlando
  • 年月日: 2010-11-18