A New System to Study the Control of Epidermal Growth

描述(申请人提供)：精确的时间控制表皮分化对于皮肤的正常形成是必不可少的。这一过程的中断可能导致各种皮肤病和肿瘤的发生。例如，表皮内过早和延迟的分化可能导致与银屑病相关的增生性疾病，而来自底层真皮的信号可以确定与鳞癌相关的异常角质形成细胞的形成。因此，识别控制表皮分化时机的细胞和分子机制是了解皮肤病的原因和设计创新治疗策略的先决条件。这项建议将评估利用一种新的禽类嵌合系统来确定神经脊来源的真皮调节表皮发育的分子机制的可行性，并开发新的治疗方法来控制表皮分化的时机。鹌鹑和鸭子胚胎的生长速度不同，移植后，形成颅面真皮的供体神经嵴细胞通过加速包括骨形态发生蛋白(BMP)信号通路成员在内的基因表达，诱导宿主表皮结构(如羽毛)的过早形成。相反，在相互移植中，供体真皮推迟了寄主表皮基因表达的时间，并延缓了羽毛的组织发生。我们假设神经脊来源的间充质通过调节真皮和表皮之间的BMP信号来控制羽毛形态发生的时间。为了验证我们的假设，我们将结合在QUCK(鹌鹑供体真皮，鸭子宿主表皮)中产生提前羽芽和在Duail(鸭子供体真皮，宿主表皮)中产生延迟羽芽的鹌鹑-鸭子嵌合系统与将在供体真皮和/或宿主来源的表皮中特异性地调节BMP信号的分子方法相结合。我们的近期目标是“挽救”嵌合体表皮的过早或延迟发育，这对设计基于分子的疗法来治疗皮肤病具有潜在的临床意义，这些皮肤病的病因是表皮分化的时间被打乱。虽然这项建议本质上是探索性的，但长期目标是创建一个有效的实验范式，用于解决表皮发育中的许多关键问题，如与细胞增殖、黑素生成和角质化调节有关的问题。

DESCRIPTION (provided by applicant): Precise temporal control of epidermal differentiation is essential for proper formation of the skin. Disruptions to this process can result in a variety of skin diseases and tumorigenesis. For example, premature and delayed differentiation within the epidermis can lead to hyperplasias associated with psoriasis, and signals from the underlying dermis can establish when aberrant keratinocytes form in association with squamous carcinomas. Thus, identifying cellular and molecular mechanisms that control the timing of epidermal differentiation is a prerequisite for understanding the causes of skin disorders and for devising innovative treatment strategies. This proposal will assess the feasibility of utilizing a new avian chimeric system to identify molecular mechanisms by which the neural crest-derived dermis regulates epidermal development, and to develop novel therapeutic approaches for controlling the timing of epidermal differentiation. Quail and duck embryos have divergent growth rates, and following transplantation, quail donor neural crest cells, which give rise to the craniofacial dermis, induce premature formation of host epidermal structures such as feathers by accelerating the expression of genes including members of the Bone Morphogenetic Protein (BMP) signaling pathway. Conversely in reciprocal transplants, duck donor dermis delays the timing of host epidermal gene expression and retards feather histogenesis. We hypothesize that neural crest-derived mesenchyme controls the timing of feather morphogenesis by regulating BMP signaling between the dermis and epidermis. To test our hypothesis we will combine the quail-duck chimeric system, which produces premature feather buds in quck (quail donor dermis, duck host epidermis) and delayed feather buds in duail (duck donor dermis, quail host epidermis) with molecular approaches that will specifically modulate BMP signaling in donor dermis and/or host-derived epidermis. Our immediate goal is to "rescue" the premature or delayed development of the epidermis in chimeras, which has potential clinical implications for devising molecular-based therapies to treat skin disorders that have as their etiology a disruption to the timing of epidermal differentiation. While this proposal is exploratory in nature, a long-term goal is to create a potent experimental paradigm for addressing numerous critical issues in epidermal development such as those that relate to the regulation of cell proliferation, melanogenesis, and keratinization.