A New System to Study the Control of Epidermal Growth

描述（由申请人提供）：表皮分化的精确时间控制对于皮肤的正确形成至关重要。这一过程的中断可导致各种皮肤病和肿瘤发生。例如，表皮内的过早和延迟分化可导致与银屑病相关的增生，并且当与鳞状细胞癌相关的异常角质形成细胞形成时，可建立来自下层真皮的信号。因此，识别控制表皮分化时间的细胞和分子机制是理解皮肤病原因和设计创新治疗策略的先决条件。该提案将评估利用新的禽类嵌合系统来鉴定神经嵴衍生的真皮调节表皮发育的分子机制的可行性，并开发用于控制表皮分化时间的新的治疗方法。鹌鹑和鸭胚胎具有不同的生长速率，并且在移植后，鹌鹑供体神经嵴细胞（其产生颅面真皮）通过加速包括骨形态发生蛋白（BMP）信号通路的基因的表达诱导宿主表皮结构（例如羽毛）的过早形成。相反，在相互移植中，鸭供体真皮延迟宿主表皮基因表达的时间，并延缓羽毛组织发生。我们推测，神经嵴来源的间充质通过调节真皮和表皮之间的BMP信号传导来控制羽毛形态发生的时间。为了验证我们的假设，我们将联合收割机结合鹌鹑-鸭嵌合系统，其在quck（鹌鹑供体真皮，鸭宿主表皮）中产生过早的羽芽，在duail（鸭供体真皮，鹌鹑宿主表皮）中产生延迟的羽芽，并结合分子方法，其将特异性地调节供体真皮和/或宿主衍生表皮中的BMP信号传导。我们的近期目标是“拯救”嵌合体中表皮的过早或延迟发育，这对于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中断。虽然该提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，以解决表皮发育中的许多关键问题，例如与细胞增殖、黑素生成和角化调节相关的问题。

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.