Mouse nude locus and skin development

小鼠裸位点和皮肤发育

• 批准号: 8104009
• 负责人: JANICE L BRISSETTE
• 金额: $ 34.11万
• 依托单位: SUNY DOWNSTATE MEDICAL CENTER
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8104009
• 关键词: Affect; Ally; Animals; Automobile Driving; Binding; Biological Assay; Cell Proliferation; Cell Surface Proteins; Cell physiology; Cells; Charge; Complement; Complex; Congenital Alopecia; Cultured Cells; Cutaneous; DNA Binding Domain; Defect; Destinations; Development; Developmental Process; Differentiation and Growth; Disease; Engineering; Environment; Epidermis; Epithelial; Epithelial Cells; Epithelium; Family; Gap Junctions; Genes; Genetic; Goals; Growth; Growth Factor; Hair; Hair follicle structure; Hazardous Chemicals; Health; Human; In Vitro; Knockout Mice; Ligands; Mammary gland; Mature T-Lymphocyte; Mediating; Membrane; Methods; Microarray Analysis; Mitogens; Modeling; Molecular; Morphogenesis; Mus; Nail plate; Natural regeneration; Nude Mice; Orthologous Gene; Pathology; Pathway interactions; Pattern; Phenotype; Pigmentation physiologic function; Pigments; Play; Population; Process; Production; Promoter Regions; Property; Proteins; Recruitment Activity; Regulation; Relative (related person); Research; Rodent; Role; Signal Transduction; Site; Skin; Skin Pigmentation; Skin part; Structure; System; T-Cell Immunodeficiency; Testing; Thymus Gland; Tissues; Transactivation; Transgenic Mice; Ultraviolet Rays; Water; Winged Helix; Work; axon guidance; base; cell type; extracellular; insight; keratinocyte; melanocyte; member; notch protein; pathogen; programs; repaired; self-renewal; skin morphogenesis; trait; transcription factor

DESCRIPTION (provided by applicant): The long-term objective of this research is to gain a better understanding of the regulation of skin development. The goal of this project is to elucidate the function of Foxn1, a member of the winged- helix/forkhead family of transcription factors. In rodents, the loss of Foxn1 function results in the nude phenotype, which is characterized by the abnormal morphogenesis of the skin, thymus, mammary gland, and nails. Based on our work to date, we have developed the following model of Foxn1 function. In the skin, epithelial cells induce Foxn1 as they lose the ability to multiply and initiate terminal differentiation. In a site- dependent manner, Foxn1 then promotes up to three developmental processes: the differentiation of its host cells, the melanization of its host cells by melanocytes, and the growth of its surrounding host epithelium. To regulate these processes, Foxn1 activates intercellular signaling systems, thereby inducing epithelial cells to cooperate with each other and pigment cells. According to this model therefore, Foxn1 acts as a regulatory nexus, coordinating the growth, differentiation, and pigmentation of cutaneous tissues. To explain how this Foxn1 nexus works, we have developed the following hypothesis: that Foxn1 organizes cells into cooperative units by activating two types of extracellular signals - diffusible signals, which are responsible for Foxn1's long-range actions (e.g., the induction of cell proliferation and the recruitment of melanocytes to epithelial cells), and cell-bound signals, which are responsible for Foxn1's short-range actions (e.g., the flagging of epithelial cells for pigmentation and the locking of pigmentary connections into place). To test this hypothesis and the underlying model, the downstream effectors of Foxn1 will be elucidated. The specific aims of the project are as follows: 1) to isolate and characterize Foxn1 effectors, 2) to determine the significance of the effectors to the Foxn1 pathway and skin, and 3) to dissect the molecular mechanisms by which Foxn1 regulates its effectors. In humans, FOXN1 is conserved in sequence and function, suggesting it employs a conserved set of downstream effectors. Thus, by identifying Foxn1 effectors, the project should provide insight into disorders associated with the abnormal growth, differentiation, or activity of melanocytes and epithelial cells. PUBLIC HEALTH RELEVANCE: This project will elucidate fundamental mechanisms by which the skin develops and regenerates its protective epithelial traits. Specifically, the work will delineate a genetic pathway that drives and coordinates the growth, differentiation, and pigmentation of the skin's external structures. In the short term, the project will explain in part how the skin produces and assembles its barrier to the environment, which provides essential protection against pathogens, hazardous chemicals, ultraviolet light, and water loss. Over the long term, the project will provide insight into how skin may be clinically generated or manipulated, thus facilitating methods for the replacement or repair of damaged and diseased skin.

描述（由申请人提供）：本研究的长期目标是更好地了解皮肤发育的调节。该项目的目标是阐明 Foxn1 的功能，Foxn1 是转录因子翼状螺旋/叉头家族的成员。在啮齿类动物中，Foxn1 功能的丧失会导致裸表型，其特征是皮肤、胸腺、乳腺和指甲的形态发生异常。根据我们迄今为止的工作，我们开发了以下 Foxn1 函数模型。在皮肤中，上皮细胞失去增殖和启动终末分化的能力，从而诱导 Foxn1。然后，Foxn1 以位点依赖性方式促进多达三个发育过程：其宿主细胞的分化、黑素细胞对其宿主细胞的黑化以及其周围宿主上皮的生长。为了调节这些过程，Foxn1 激活细胞间信号系统，从而诱导上皮细胞彼此以及色素细胞合作。因此，根据该模型，Foxn1 充当调节纽带，协调皮肤组织的生长、分化和色素沉着。为了解释 Foxn1 连接的工作原理，我们提出了以下假设：Foxn1 通过激活两种类型的细胞外信号（可扩散信号）将细胞组织成协作单位，这些信号负责 Foxn1 的远程作用（例如，诱导细胞增殖）以及黑色素细胞向上皮细胞的募集）和细胞结合信号，这些信号负责 Foxn1 的短程作用（例如，标记上皮细胞的色素沉着和将色素连接锁定到位）。为了检验这一假设和基础模型，将阐明 Foxn1 的下游效应器。该项目的具体目标如下：1）分离和表征Foxn1效应器，2）确定效应器对Foxn1通路和皮肤的重要性，3）剖析Foxn1调节其效应器的分子机制。在人类中，FOXN1 在序列和功能上是保守的，这表明它采用了一组保守的下游效应器。因此，通过识别 Foxn1 效应子，该项目应该能够深入了解与黑素细胞和上皮细胞的异常生长、分化或活性相关的疾病。公共健康相关性：该项目将阐明皮肤发育和再生其保护性上皮特征的基本机制。具体来说，这项工作将描绘出驱动和协调皮肤外部结构的生长、分化和色素沉着的遗传途径。在短期内，该项目将部分解释皮肤如何产生和组装其对环境的屏障，这提供了针对病原体、危险化学品、紫外线和水分流失的基本保护。从长远来看，该项目将深入了解如何在临床上生成或操纵皮肤，从而促进更换或修复受损和患病皮肤的方法。