Novel regulators of skin development and Foxn1 function

皮肤发育和 Foxn1 功能的新型调节因子

• 批准号: 7461074
• 负责人: JANICE L BRISSETTE
• 金额: $ 37.66万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7461074
• 关键词: Animals; Biochemical; Biological Assay; Biological Models; Cells; Charge; Complement; Complex; Congenital Alopecia; Cultured Cells; Cutaneous; DNA Binding Domain; Defect; Development; Developmental Process; Differentiation and Growth; Disease; Dissection; Environment; Epidermis; Epithelial; Epithelial Cells; Epithelium; Exhibits; Family; Gap Junctions; Gene Expression; Genetic; Genetic Screening; Goals; Growth; Growth Factor; Hair; Hair follicle structure; Hazardous Chemicals; Human; Individual; Link; Mammary gland; Mature T-Lymphocyte; Methods; Modeling; Molecular; Morphogenesis; Mus; Mutation; Nail plate; Natural regeneration; Nature; Nexus (resin cement); Organ; Orthologous Gene; Other Genetics; Output; Pathology; Pathway interactions; Pattern; Phenotype; Physiological; Pigmentation physiologic function; Pigments; Play; Process; Production; Property; Proteins; Purpose; Recruitment Activity; Research; Rodent; Role; Screening procedure; Side; Signal Transduction; Site; Skin; Skin Pigmentation; Skin part; Structure; System; T-Cell Immunodeficiency; Testing; Thymus Gland; Transactivation; Transcription Coactivator; Ultraviolet Rays; Water; Winged Helix; Work; base; cell type; genetic manipulation; insight; keratinocyte; melanocyte; member; novel; pathogen; programs; repaired; research study; self-renewal; size; trait; transcription factor

DESCRIPTION (provided by applicant): The goal of this project is to identify the molecular partners of Foxn1 and to elucidate their contributions to skin development. Foxn1 is a transcription factor containing a winged-helix DNA-binding domain and a negatively charged transactivation domain. In rodents, the loss of Foxn1 function results in the nude phenotype, which is characterized by the abnormal morphogenesis of the skin, thymus, and mammary gland. To promote skin development, Foxn1 performs an unusual function, which was delineated by us in previous studies. Foxn1 becomes activated as epithelial cells initiate terminal differentiation in the epidermis and hair follicles. In a site-dependent manner, Foxn1 then plays up to three roles: 1) it allows its host cell to differentiate properly, 2) it stimulates the host cell's neighbors to divide, and 3) it recruits melanocytes to the host cell, thus identifying its host as a target for pigmentation. Through this combination of actions, Foxn1 enables groups of cells to work in concert and drives epithelial growth, differentiation, and pigmentation forward together. Presumably, Foxn1 itself works in concert with other factors, which provide it with information, determine its level of activity, direct it to specific targets, or function side-by-side with it in synergistic fashion. Undoubtedly, Foxn1 requires these partners for efficacy, making the partners of Foxn1 essential to the morphogenesis of the skin and other organs. During the course of this project, we will identify the partners of Foxn1 using two approaches, one genetic, the other biochemical. In the genetic approach, we will screen for mutations that modulate the activity or output of Foxn1. The screen will employ a novel model system, which we have developed for the study. In the biochemical approach, we will purify Foxn1 protein complexes from keratinocytes and dissect the individual components. Once partners are identified, we will determine how they contribute to the actions of Foxn1 and the morphogenesis of the skin. In humans, FOXN1 is conserved in sequence and function, suggesting a like conservation of partners. Accordingly, by elucidating the partnerships of Foxn1, the project should provide insight into the development of normal and diseased human skin, most especially, the disorders marked by the aberrant proliferation, differentiation, or pigmentation of epithelial cells. Project Narrative: This project will elucidate fundamental mechanisms by which the skin develops and regenerates its protective epithelial traits. Specifically, the work will delineate a genetic network 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）：这个项目的目标是确定Foxn1的分子伴侣，并阐明它们对皮肤发育的贡献。Foxn1是一种转录因子，包含一个带翼螺旋的dna结合域和一个带负电荷的转激活域。在啮齿类动物中，Foxn1功能的丧失导致裸表型，其特征是皮肤、胸腺和乳腺的形态发生异常。为了促进皮肤发育，Foxn1发挥了一种不同寻常的功能，这是我们在之前的研究中所描述的。当上皮细胞在表皮和毛囊中开始终末分化时，Foxn1被激活。Foxn1以位点依赖的方式发挥三个作用：1)允许宿主细胞正常分化，2)刺激宿主细胞的邻近细胞分裂，3)将黑素细胞招募到宿主细胞，从而将宿主识别为色素沉着的靶标。通过这些作用的组合，Foxn1使细胞群协同工作，共同推动上皮细胞的生长、分化和色素沉着。据推测，Foxn1本身与其他因素协同工作，这些因素为其提供信息，决定其活动水平，指导其特定目标，或以协同方式与之并肩工作。毫无疑问，Foxn1需要这些伴侣才能发挥作用，这使得Foxn1的伴侣对皮肤和其他器官的形态发生至关重要。在这个项目的过程中，我们将使用两种方法来确定Foxn1的伙伴，一种是遗传的，另一种是生化的。在遗传方法中，我们将筛选调节Foxn1活性或输出的突变。屏幕将采用一种新的模型系统，这是我们为这项研究开发的。在生化方法中，我们将从角质形成细胞中纯化Foxn1蛋白复合物并解剖单个成分。一旦确定了伴侣，我们将确定他们如何影响Foxn1的作用和皮肤的形态发生。在人类中，FOXN1在序列和功能上是保守的，这表明伴侣也有类似的保守性。因此，通过阐明Foxn1的伙伴关系，该项目应该提供对正常和患病人类皮肤发育的深入了解，尤其是以上皮细胞异常增殖、分化或色素沉着为特征的疾病。项目描述：本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，这项工作将描绘一个驱动和协调皮肤外部结构的生长、分化和色素沉着的遗传网络。在短期内，该项目将在一定程度上解释皮肤如何产生和组装其对环境的屏障，这为抵御病原体、有害化学物质、紫外线和水分流失提供了必要的保护。从长远来看，该项目将深入了解如何在临床上生成或操作皮肤，从而促进替代或修复受损和病变皮肤的方法。