MOUSE NUDE LOCUS AND EPIDERMAL DEVELOPMENT

小鼠裸位点和表皮发育

• 批准号: 6375111
• 负责人: JANICE L BRISSETTE
• 金额: $ 24.65万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6375111
• 关键词: cell differentiation; cell growth regulation; cell proliferation; developmental genetics; gene mutation; genetically modified animals; growth factor; histogenesis; human tissue; keratinocyte; laboratory mouse; paracrine; skin; tissue /cell culture; transcription factor; transforming growth factors

The goal of this research is to gain a better understanding of the regulation of skin development. As self-renewing structures, the epidermis and hair follicles require a balance between keratinocyte cell division and terminal differentiation for their formation and maintenance. To gain insight into this process, the applicants are studying the function of Whn (Winged-helix nude), the product of the mouse nude locus and a putative member of the winged-helix/forkhead family of transcription factors. Loss-of-function mutations in whn result in the nude phenotype, which is characterized by the failure to produce visible hair, the abnormal formation of the epidermis, and the absence of a thymus. Based on their previous studies, the applicants have constructed a model to explain Whn's role in skin morphogenesis. They find that whn expression is induced, as keratinocytes arrest growth and initiate terminal differentiation. They postulate that Whn: 1) promotes the transition from proliferation to differentiation by activating genes associated with the differentiation program; and 2) induces differentiating cells to secrete growth factors. These growth factors then stimulate neighboring keratinocytes, which lack the Whn protein, to proliferate. As a result of this paracrine mechanism, a differentiating keratinocyte is replaced as it leaves the proliferative compartment, and the balance between multiplying and differentiating cells is maintained. The aim of this proposal is to test this model and provide a basic framework for the elucidation of Whn's mechanism of action. To assess Whn's direct and paracrine effects, transgenic mice will be generated in which Whn expression is specifically targeted to either proliferating or differentiating keratinocytes. Since the investigators have acquired preliminary evidence that Whn stimulates the expression of transforming growth factor-a (TGF-a), the ability of Whn to bind to the TGF-a promoter and activate transcription will be evaluated. Lastly, they and others have isolated the human homolog of whn, and find that the human and murine Whn proteins are 85 percent identical. As a first step in the characterization of this homolog, the Whn expression pattern will be examined in normal and diseased human skin. Given the pleiotropic effects of murine whn, the human homolog they believe could play a role in diseases associated with hyperproliferation, hair loss, or aberrant differentiation.

这项研究的目的是为了更好地了解 皮肤发育的调节。 作为自我更新的结构， 表皮和毛囊需要角质形成细胞之间的平衡 分裂和终末分化的形成和 维护。 为了深入了解这一过程，申请人 研究 Whn（翼螺旋裸体）的功能，该产物是 小鼠裸基因座和翼螺旋/叉头的假定成员 转录因子家族。 whn 的功能丧失突变 导致裸表型，其特征是未能 产生可见的毛发、表皮的异常形成以及 缺乏胸腺。 根据申请人之前的研究， 构建了一个模型来解释 Whn 在皮肤形态发生中的作用。 他们发现当角质形成细胞停止生长时，诱导表达 并启动终末分化。 他们假设当：1) 促进从增殖到分化的转变 激活与分化程序相关的基因；和 2) 诱导分化细胞分泌生长因子。 这些成长 然后刺激邻近的角质形成细胞，这些细胞缺乏 Whn 蛋白质，增殖。 由于这种旁分泌机制， 分化的角质形成细胞在离开增殖细胞后被替换 隔间，以及乘法和微分之间的平衡 细胞得到维持。 该提案的目的是测试该模型并 为阐明Whn的机制提供了一个基本框架 行动。为了评估 Whn 的直接效应和旁分泌效应，转基因小鼠 将生成其中 Whn 表达式专门针对 角质形成细胞增殖或分化。 自从 调查人员已获得初步证据表明 Whn 刺激了 转化生长因子-a (TGF-a) 的表达，Whn 的能力 与 TGF-a 启动子结合并激活转录 评价。 最后，他们和其他人分离出了人类同源物 并发现人类和小鼠的 Whn 蛋白占 85% 完全相同的。 作为表征该同系物的第一步， 将在正常人和患病人类中检查何时表达模式 皮肤。 鉴于鼠whn的多效性作用，人类同源物 他们认为可能在与以下疾病相关的疾病中发挥作用 过度增殖、脱发或异常分化。