A New System to Study the Control of Epidermal Growth

描述（由申请人提供）：精确控制表皮分化的时间对于皮肤的正确形成至关重要。这一过程的破坏可导致各种皮肤疾病和肿瘤发生。例如，表皮内过早和延迟分化可导致与银屑病相关的增生，当与鳞状癌相关的异常角质形成细胞形成时，来自底层真皮的信号可建立。因此，确定控制表皮分化时间的细胞和分子机制是理解皮肤疾病原因和设计创新治疗策略的先决条件。本研究将评估利用一个新的鸟类嵌合系统来确定神经嵴源性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间。鹌鹑和鸭胚胎具有不同的生长速度，移植后，鹌鹑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，从而形成颅面真皮。相反，在互惠移植中，鸭供体真皮延迟了宿主表皮基因表达的时间，阻碍了羽毛的组织发生。我们假设神经冠源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，我们将结合鹌鹑-鸭嵌合系统，该系统在鹌鹑（鹌鹑供体真皮，鸭子宿主表皮）中产生过早的羽毛芽，在双鹌鹑（鸭子供体真皮，鹌鹑宿主表皮）中产生延迟的羽毛芽，并采用分子方法特异性地调节供体真皮和/或宿主衍生表皮中的BMP信号。我们的直接目标是“拯救”嵌合体中过早或延迟的表皮发育，这对于设计基于分子的疗法来治疗因表皮分化时间中断而导致的皮肤疾病具有潜在的临床意义。虽然这一建议本质上是探索性的，但其长期目标是创建一个强有力的实验范例，以解决表皮发育中的许多关键问题，如与细胞增殖、黑色素形成和角化相关的调节。

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.