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 调节皮肤发育。 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， 上维护 为了深入了解这一过程，申请人 研究Whn（Winged-helix nude）的功能， 小鼠裸基因座和翼螺旋/叉头的推定成员 转录因子家族。whn基因功能缺失突变 导致裸表型，其特征在于不能 产生可见的毛发，表皮的异常形成，以及 没有胸腺。 根据他们以前的研究，申请人 已经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， 并启动终末分化。 他们假设Whn：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。 这些生长 然后，这些因子刺激邻近的角质形成细胞， 蛋白质，增殖。 由于这种旁分泌机制， 分化的角质形成细胞被替换，因为它离开增殖的角质形成细胞。 以及倍增和差异化之间的平衡 细胞保持。 本提案的目的是检验这一模式， 提供了一个基本的框架，为阐明Whn的机制， 行动上为了评估Whn的直接和旁分泌效应， 将产生其中Whn表达特异性靶向 增殖或分化角质细胞。 以来 调查人员已经获得了初步证据，表明Whn刺激了 转化生长因子-α（TGF-α）的表达、Whn 与TGF-α启动子结合并激活转录将是 评估。 最后，他们和其他人已经分离出了 whn，并发现人类和小鼠的Whn蛋白是85%， 一模一样 作为表征该同系物的第一步， Whn的表达模式将在正常和患病的人中进行检查 皮肤 鉴于小鼠whn的多效性，人类同源物 他们认为可能在与 过度增殖、脱发或异常分化。