Development of a new therapy and create a mouse model for psoriasis with MAPK signal transmission system

利用MAPK信号传输系统开发银屑病新疗法并创建小鼠模型

• 批准号: 18591247
• 负责人: TARUTANI Masahito
• 金额: $ 2.49万
• 依托单位: Hyogo College of Medicine (2007)Osaka University (2006)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591247/
• 关键词: MAPK; Raf-1; skin; psoriasis; tamoxifen; IL-18; mouse model; AKT

Activation of MAP Kinase in skin plays a critical role for skin proliferation. Raf is one of the upstream effectors of MAPK signaling that induce epidermal hyperplasia. We previously characterized Kl4RafERtm transgenic mice bearing the 4-hydroxytamoxifen (4OHT)-responsive mutant ER ligand binding domain-Raf fusion gene under control of the keratin 14 promoter. A single topical application of 4OHT induced the epidermis-specific expression of Phosphorylated active ERK 1/2, a downstream factor of Raf signaling, in those mice within 8-12 hrs. Massive hyperplasia with hyperkeratosis and suppressed differentiation of the epidermis developed within 7 days. The inflammatory changes were also seen in these mice with 4-OHT treatments. We imported these mice from Dr. khavari rab at U. S. A.. At first we checked whether applying MAPK inhibitors in mouse skin reduced these phenomenon. We applied PD98059, genistein, LY294002, apigenin, SB202190, and SB203580, the MAPK and related gene inhibitors, with 4-hydroxy-tamoxifen (4-OHT) in Kl4RafERtm transgenic mice skin. But there is no significant difference between both-applied and only 4-hydroxy-tamoxifen applied transgenic mice skin. Next we applied cortico steroids ointment with 4-OHT in these mice. The acantosis of the skin and inflammation were diminished with treatment of cortico steroids. To investigate these skin condition, we purified the protein in 4-OHT treated skin lesions and checked cytokine level. IL-18, IL-15 and MCP-1 levels were increased in the skin lesions and IFN-γ and IL-17 were induced in T cells of the draining lymph nodes. Thus, the induction of Raf in the epidermis causes not only keratinocyte hyper proliferation but also psoriasis-like inflammatory conditions of the skin.

皮肤中MAP激酶的激活在皮肤增殖中起关键作用。Raf是诱导表皮增生的MAPK信号的上游效应子之一。我们先前表征了在角蛋白14启动子的控制下携带4-羟基他莫昔芬（4 OHT）响应性突变体ER配体结合结构域-Raf融合基因的Kl 4 RafERtm转基因小鼠。单次局部应用4 OHT在8- 1/2小时内诱导这些小鼠中磷酸化活性ERK 1/2（Raf信号传导的下游因子）的表皮特异性表达。7天内出现大量增生伴角化过度和表皮分化抑制。在4-OHT治疗的这些小鼠中也观察到炎症变化。我们从哈佛大学的卡瓦里·拉布博士那里引进了这些老鼠。S. A..首先，我们检查了在小鼠皮肤中应用MAPK抑制剂是否会减少这些现象。我们在Kl 4 RafERtm转基因小鼠皮肤中应用了PD 98059、染料木黄酮、LY 294002、芹菜素、SB 202190和SB 203580（MAPK及相关基因抑制剂）以及4-羟基-他莫昔芬（4-OHT）。但同时应用4-羟基-他莫昔芬和仅应用4-羟基-他莫昔芬的转基因小鼠皮肤之间没有显著差异。接下来，我们在这些小鼠中应用皮质类固醇软膏与4-OHT。皮质类固醇治疗后皮肤棘突和炎症减轻。为了研究这些皮肤状况，我们纯化了4-OHT治疗的皮肤病变中的蛋白质并检查了细胞因子水平。皮损中IL-18、IL-15和MCP-1水平升高，引流淋巴结T细胞中IFN-γ和IL-17被诱导。因此，表皮中Raf的诱导不仅引起角质形成细胞过度增殖，而且引起皮肤的银屑病样炎性病症。

项目成果

AKTシグナルの活性化により引き起こされる血管腫と表皮肥厚

AKT 信号激活引起的血管瘤和黑棘皮病

• 发表时间: 2006
• 作者: 樽谷 勝仁;村山 一茂;他
• 通讯作者: 他

Acanthosis and Hemangiona due to activation of the AKT signaling.

AKT 信号激活导致棘皮症和血管瘤。

• 发表时间: 2006
• 作者: Tarutani M;Murayama K;et. al.
• 通讯作者: et. al.

DNAマイクロアレイを用いた表皮の分化に関与する遺伝子の検索

使用 DNA 微阵列寻找参与表皮分化的基因

• 发表时间: 2007
• 期刊: 角化症研究会記録集 21
• 作者: 樽浴 勝仁;片山 一朗
• 通讯作者: 片山 一朗

An interim report of the Cooperative study at University, hospital and clinic about the medication of the cyclosporine in the treatment of psoriasis.

大学、医院和诊所关于环孢素治疗牛皮癣的合作研究的中期报告。

• 发表时间: 2007
• 作者: Tarutani M;Sano S;Katayama I
• 通讯作者: Katayama I

Utility of the anti-Histamine drugs for itchy by psoriasis

抗组胺药物治疗牛皮癣瘙痒的效用

• 发表时间: 2007
• 期刊: Hihu allergy frontier 5(2)
• 作者: Yoshida Y;Tarutani M;Sano S;Katayama I;Nemoto O;Nakayama J;Tarutani M Katayama I;Tarutani M
• 通讯作者: Tarutani M