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Analysis of Mutated SERCA2b transgenic mouse

突变SERCA2b转基因小鼠分析

基本信息

批准号：
17390309
负责人：
IIZUKA Hajime
金额：
$ 6.98万
依托单位：
Asahikawa Medical College
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

项目摘要

Mutations in the sarcoendoplasmic reticulum calcium ATPase 2b (SERCA2b) gene (ATP2A2) and the resulting defects in the SERCA2b cause an autosomal dominant genetic skin disease, Darier disease. Among the various point mutations causing Darier disease L321F mutation is unique, because this mutation shows the remarkably reduced sensitivity to the feedback inhibition of the transport cycle by accumulated luminal calcium. We have generated L321F transgenic mouse which showed no remarkable phenotype abnormality with apparently normal hair growth. Neither heat treatment nor tape-stripping ptrocedure resulted in Darier type acantholytic or dyskeratotic changes. These results indicate that other compensatory mechanism of keratinocyte calcium homeostasis exist in mouse keratinocytes to abrogate the dominant-negative effect of L321F. We have also performed analysis of ATP2C1, another calcium pump located in Golgi apparatus, the mutation of which causes another autosomal dominant skin disorder, Ha … More iley-Hailey disease. Immunohistochemical analysis disclosed that ATP2C1 is specifically localized at the basal cell layer. Neither detachment of keratinocytes from culture dish nor treatment with high concentrations of calcium suppressed ATP2C1 expression, while both procedures induced keratinocyte differentiation markers, K10 keratin and involucrin. Knockdown of ATP2C1 induced these differentiation markers of keratinocytes. These results suggest that ATP2C1 plays an essential role for basal keratinocytes to keep in the undifferentiated state and that its reduction evokes differentiation. Taken together, our results indicate that calcium homeostasis affects differentiation of keratinocytes and the mutation of ATP2A2 and ATP2C1 hampers the essential process of keratinocytes resulting in Darier disease and Hailey-Hailey disease, respectively Altered kinetic properties of calcium-regulating pumps will cause different types of perturbation in tracellular calcium homeostasis of keratinocytes affecting their differentiation process. Less

肌内质网钙ATPase 2b(SERCA2b)基因(ATP2A2)的突变和由此导致的SERCA2b缺陷导致了一种常染色体显性遗传性皮肤病，Darier病。在导致Darier病的各种点突变中，L321F突变是独一无二的，因为该突变对鲁米那钙积累对运输周期的反馈抑制的敏感性显著降低。我们获得了L321F转基因小鼠，没有明显的表型异常，毛发生长明显正常。热处理和剥带处理均未引起Darier型棘层松解或角化不良改变。这些结果表明，在小鼠角质形成细胞中存在其他角质形成细胞钙稳态的代偿机制，以消除L321F的显性-负性作用。我们还分析了位于高尔基体的另一种钙泵ATP2C1，它的突变导致了另一种常染色体显性遗传性皮肤病，Ha…更多的伊利-海利病。免疫组织化学分析表明，ATP2C1特异性定位于基底细胞层。无论是角质形成细胞脱离培养皿还是高浓度钙处理都不能抑制ATP2C1的表达，而两种方法都能诱导角质形成细胞分化标记物K10角蛋白和总蛋白的表达。ATP2C1基因敲除可诱导角质形成细胞的这些分化标记物。这些结果表明，ATP2C1在基底层角质形成细胞维持未分化状态中起着重要作用，它的减少引起分化。综上所述，我们的结果表明，钙稳态影响角质形成细胞的分化，ATP2A2和ATP2C1突变阻碍了角质形成细胞的基本过程，分别导致Darier病和Hailey-Hailey病，钙调节泵动力学特性的改变将导致不同类型的角质形成细胞内钙稳态的扰动，影响其分化过程。较少

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Plectin deficient epidermolysis bullosa simplex with 27-year-history of muscular dystrophy.

Plectin 缺陷型单纯性大疱性表皮松解症，有 27 年肌营养不良史。

DOI：
发表时间：
2005
期刊：
Journal of dermatological science (Amsterdam)
影响因子：
0
作者：
Yoshie Takahashi;F. Rouan;J. Uitto;A. Ishida‐Yamamoto;H. Iizuka;K. Owaribe;M. Tanigawa;N. Ishii;S. Yasumoto;T. Hashimoto
通讯作者：
T. Hashimoto

Up-regulation of loricrinexpression by cell adhesion molecule nectin-1 through Rap-ERK signaling in keratinocytes.

角质形成细胞中细胞粘附分子 nectin-1 通过 Rap-ERK 信号传导上调 loricrin 表达。

DOI：
发表时间：
2007
期刊：
282
影响因子：
0
作者：
Wakamatsu K;Ogita H;Okabe N;Irie K;Tanaka-Okamoto M;Ishizaki H;Ishida Yamamoto A;Iizuka H;Miyoshi J;Takai Y
通讯作者：
Takai Y

Congenital acantholytic dyskeratotic epidermal naevus following Blaschko s lines versus segmental Darier s disease.

Blaschko 线后的先天性棘层松解性角化不良性表皮痣与节段性 Darier 病。