Research of the fimction of SOCS3 in the pathogenesis ofpscriasis using keratinocyte specific SOCS3 knozkout mice

角化细胞特异性SOCS3基因敲除小鼠研究SOCS3在牛皮癣发病机制中的作用

• 批准号: 18390314
• 负责人: HASHIMOTO Koji
• 金额: $ 11.14万
• 依托单位: Ehime University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 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-18390314/
• 关键词: psoriasis; keratinocytes; SOCS3; STAT3; keratinocyte-specific knockout mouse; regeneration; RT-PCR; epidermal thickenin

STAT3 is a latent cytoplasmic protein that conveys signals to the nucleus upon stimulation with IL-6, EGF and many other growth factors. STAT3 plays critical roles in biological function such as cell proliferation, migration and so on. Suppressors of cytokine signaling (SOCS) regulate the strength of cytokine signals. SOCS3 is strongly induced by a variety of cytokines and other stimulators. The suppressive effect of SOCS3 has been shown to be relatively specific to STAT3. Therefore we investigated the role of SOCS3 in epidermal keratinocytes. Since germline targeting of the SOCS3 gene resulted in embryonic lethality, we generated keratinocyte-specific SOCS3-deficient mice (KS-SOCS3-/-mice) using Cre/loxP technology in combination with the keratin 5 promoter. KS-SOCS3-/-mice were viable and their skin appeared normal at birth. No histological alterations were found in skin of KS-SOCS3-/-mice, however, after 20 weeks, their skin was red and scaly, hyperkeratotic lesions developed in the … More ear, tail and the back skin in some mice. Histological analysis of skin lesions showed a marked hyperplasia, elongation of rete ridge, loss of granular layer and parakeratosis. These phenotype and histology show a strong resemblance to human psoriasis lesions. Next we utilized tape stripping which is a mild form of epidermal injury. KS-SOCS3-/-mice developed scaly lesions as early as 4days after stripping, whereas wild type mice showed a mild phenotype. The phenotype found in KS-SOCS3-/-mice prolonged until 14 days after stripping when wild type mice showed no obvious clinical phenotype. Tape stripping-induced lesions of KS-SOCS3-/-mice also showed histological feature of human psoriasis. Keratinocytes in the epidermis of KS-SOCS3-/-mice were highly positive for Ki67. Phosphorylated STAT3 staining was strong in KS-SOCS3-/-mice compared to wild type mice. In conclusion, loss of SOCS3, an endogenous inhibitor of STAT3, in epidermal keratinocytes leads to clinical phenotype of human psoriasis. Less

STAT3是一种潜在的细胞质蛋白，在用IL-6，EGF和许多其他生长因子刺激后将信号传达到核方面。 STAT3在生物学功能中起关键作用，例如细胞增殖，迁移等。细胞因子信号传导（SOCS）的抑制剂调节细胞因子信号的强度。 SOCS3是由各种细胞因子和其他刺激剂强烈诱导的。 SOCS3的抑制作用已被证明是STAT3特别特异的。因此，我们研究了SOCS3在表皮角质形成细胞中的作用。由于SOCS3基因的种系靶向产生了胚胎致死性，因此我们使用CRE/LOXP技术与角蛋白5启动子结合使用了角质形成细胞特异性SOCS3缺陷小鼠（KS-SOCS3 - / - 小鼠）。 KS-SOCS3 - / - 小鼠的可行性，其皮肤出生时看起来正常。在KS-SOCS3 - / - 小鼠的皮肤中未发现组织学改变，但是，在20周后，它们的皮肤是红色和鳞状的，在…更早的，尾巴和背部皮肤中出现了过度性病变。皮肤病变的组织学分析显示出明显的增生，rete脊的伸长，颗粒层和Parakeratesis的丧失。这些表型和组织学表现出与人牛皮癣病变非常相似的。接下来，我们使用胶带剥离，这是一种轻度的表皮损伤形式。 KS-SOCS3 - / - 小鼠早在剥离后4天就患有鳞状病变，而野生型小鼠表现出轻度的表型。在剥离后14天内，野生型小鼠没有明显的临床表型，直到剥离后的14天，在KS-SOCS3 - / - 小鼠中发现的表型。 KS-SOCS3 - / - 小鼠的胶带剥离诱导的病变也显示了人牛皮癣的组织学特征。 KS-SOCS3 - / - 小鼠表皮中的角质形成细胞对Ki67高度阳性。与野生型小鼠相比，KS-SOCS3 - / - 小鼠的磷酸化STAT3染色强。总之，在表皮角质形成细胞中，SOCS3（SOCS3）的内源性抑制剂丧失导致人牛皮癣的临床表型。较少的

项目成果

A new skin equivalent using de-epithelialized amnion membrane

使用去上皮羊膜的新皮肤等同物

• 发表时间: 2007
• 作者: Shirakata Y;Yang L;Hashimoto K
• 通讯作者: Hashimoto K

PPARgamma is an important transcription factor in lalpha,25-dihyclroxyvitamin 03-induced involucrin expression

PPARgamma 是 lalpha,25-二羟维生素 03 诱导的外皮蛋白表达中的重要转录因子

• 发表时间: 2008
• 期刊: I Dermatol Sci 50
• 作者: Dai;X;Sayama;IC;Shirakata;Y;Tokunaru;S;Yang;L;Tohyama;M;Hirakawa;S;Hanakawa;Y;Hashimoto;K
• 通讯作者: K

PPARγ/C/EBPalpha signaling pathway plays a key role in 1,25-dihydroxyvitamin D3-induced keratinocyte differentiation.

PPARγ/C/EBPα信号通路在1,25-二羟基维生素D3诱导的角质形成细胞分化中发挥关键作用。

• 发表时间: 2006
• 作者: Y Shirakata;X Dai;S Tokumaru;Y Hanakawa;M Tohyama;L Yang;K Sayama;and K Hashimoto
• 通讯作者: and K Hashimoto

TAK I is essential for differentiation and the prevention of apoptosis in epidermis

TAK I 对于表皮分化和预防细胞凋亡至关重要

• 发表时间: 2006
• 期刊: J Biol Chem 281
• 作者: Sayama;K;Hanakawa;Y;Nagai;H;Shiralcata;Y;Dai;X;Hirakawa;S;Tokumaru;S;Tohyama;M;Yang;L;Sato;S;Shizuo;A;Hashimoto;K
• 通讯作者: K

Human corneal epithelial cell proliferation by epiregulin and its cross-induction by other EGF family members

上皮调节蛋白对人角膜上皮细胞的增殖及其与其他EGF家族成员的交叉诱导

• 发表时间: 2007
• 期刊: Mol. Vision 13
• 作者: Morita;S.;Shirakata;Y.;Shiraishi;A.Kadota;Y.;Hashimoto ;K.;Higashiyama,S.;Ohashi;Y.
• 通讯作者: Y.