Mouse nude locus and epidermal development

小鼠裸位点和表皮发育

• 批准号: 7117632
• 负责人: JANICE L BRISSETTE
• 金额: $ 31.58万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 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 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7117632
• 关键词: athymic mouse; binding proteins; biological signal transduction; bone morphogenetic proteins; cell differentiation; cell growth regulation; cell proliferation; developmental genetics; epithelium; fibroblast growth factor; gene mutation; genetically modified animals; hepatocyte growth factor; histogenesis; insulinlike growth factor; laboratory mouse; melanins; melanocyte; microarray technology; pigmentation; protein purification; protein structure function; skin; tissue /cell culture; transcription factor; transforming growth factors

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 Foxn1a 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, and mammary gland. From the project's work to date, the following model of Foxn1 function has been developed. In the skin, epithelial cells induce Foxn1 as they lose the ability to multiply and initiate terminal differentiation. Within the epithelium, Foxn1 then promotes up to three fundamental processes: the production of differentiated features, the coupling of cell division to differentiation, and the acquisition of melanin. To regulate these processes, Foxn1 activates intercellular signaling systems, thereby enabling epithelial cells to cooperate with each other and melanocytes. Thus, according to this model, Foxn1 acts as a regulatory link or nexus, coordinating the growth, differentiation, and pigmentation of cutaneous epithelia. To test this model, the downstream effectors of Foxn1 will be identified. The specific aims of the project are as follows: 1) to isolate and characterize Foxnl effectors, 2) to determine the functional significance of the effectors in the Foxn1 pathway, and 3) to dissect the molecular mechanism by which Foxn1 regulates each effector. The project will use the mouse as an experimental system, taking advantage of existing Foxn1 transgenics as well as nude mutants. In humans, FOXN1 is conserved in its sequence and function, suggesting that the human and rodent proteins act via similar pathways. Thus, by identifying Foxn1's effectors, the project may provide insight into diseases associated with abnormal pigmentation, hyperproliferation, or aberrant differentiation.

描述（由申请人提供）： 这项研究的长期目标是更好地了解皮肤发育的调节。本项目的目标是阐明转录因子翼螺旋/叉头家族成员Foxn 1a的功能。在啮齿类动物中，Foxn 1功能的丧失导致裸表型，其特征在于皮肤、胸腺和乳腺的异常形态发生。从该项目的工作至今，已经开发了以下Foxn 1功能模型。在皮肤中，上皮细胞诱导Foxn 1，因为它们失去了繁殖和启动终末分化的能力。在上皮内，Foxn 1促进了三个基本过程：分化特征的产生，细胞分裂与分化的耦合以及黑色素的获得。为了调节这些过程，Foxn 1激活细胞间信号系统，从而使上皮细胞能够相互合作和黑素细胞。因此，根据该模型，Foxn 1作为调节环节或联系，协调皮肤上皮细胞的生长、分化和色素沉着。为了测试该模型，将鉴定Foxn 1的下游效应物。该项目的具体目标如下：1）分离和表征Foxnl效应子，2）确定Foxnl通路中效应子的功能意义，以及3）剖析Foxnl调节每个效应子的分子机制。该项目将使用小鼠作为实验系统，利用现有的Foxn 1转基因以及裸突变体。在人类中，FOXN 1在其序列和功能上是保守的，这表明人类和啮齿动物蛋白通过相似的途径起作用。因此，通过鉴定Foxn 1的效应物，该项目可能会提供与异常色素沉着，过度增殖或异常分化相关的疾病的见解。