Transcription regulation in the hairless pathway

无毛通路中的转录调控

• 批准号: 6870711
• 负责人: ANDREW ENGELHARD
• 金额: $ 12.4万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-17 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6870711
• 关键词: cell cycle; clinical research; developmental genetics; gel mobility shift assay; gene expression; genetic promoter element; genetic regulatory element; genetic transcription; hair follicle; histogenesis; human tissue; immunocytochemistry; keratinocyte; nucleic acid probes; tissue /cell culture; transcription factor; vitamin D receptors

DESCRIPTION (provided by applicant): Recently much progress has been made in the understanding of hair follicle (HF) biology. The HF is a dynamic structure whose multiple compartments undergo successive rounds of complex and highly synchronized architectural reorganization during the growth (anagen), regression (catagen) and resting (telogen) phases of the hair cycle. Mutations in the hairless (hr) gene, which cause alopecia in mice and other animals and atrichia with papular lesions (APL, OMIM 209500) in humans, result in cellular and morphologic changes in the structure of the HF that have been characterized, yet little is known about the regulation of hr expression or the molecular mechanisms disrupted by h r mutations. The striking similarity in pathologies of the hairless mouse and the Vitamin D Receptor (VDR) null-mutant mouse has led to the suggestion that Hr and VDR are functionally related in the hair cycle pathway. The recent cloning of the hr promoter has revealed the presence of a putative VDR response element in a relevant location within the promoter. Although mutational analysis has identified two different grups of genes that lead to hair phenotypes, those that result in defects in follicle morphogenesis and those that exhibit deficiencies in HF cycling, we report in our preliminary data a relationship between members from each group, hairless and Lefl. Our preliminary data demonstrate that h r promoter activity can be regulated by Lefl in a beta-catenin dependent manner. This proposal aims to demonstrate that hr expression is regulated by a functional VDREin its promoter. Additionally, ince we have discovered a molecular link between the anagen and catagen phases of the hair cycle, this proposal aims to define the genetic interactions between the Wnt pathway and hairless gene expression in order to understand the molecular basis of HF cycling.

描述（由申请人提供）： 最近对毛囊（HF）的认识取得了很大进展 生物学。 HF 是一个动态结构，其多个隔室连续经历 期间进行了多轮复杂且高度同步的架构重组 头发周期的生长（生长期）、退化（退行期）和休止（休止期）阶段。 无毛 (hr) 基因突变会导致小鼠和其他动物脱发 人类无毛伴丘疹性病变（APL，OMIM 209500），导致细胞和 HF 结构的形态学变化已被表征，但很少有 了解 hr 表达的调节或 hr 破坏的分子机制 突变。 无毛小鼠和维生素 D 的病理学惊人相似 受体 (VDR) 无效突变小鼠表明 Hr 和 VDR 是 与毛发周期途径功能相关。最近克隆的 hr 启动子已 揭示了推定的 VDR 响应元素在相关位置的存在 发起人。 尽管突变分析已经确定了两组不同的基因导致 头发表型，那些导致毛囊形态发生缺陷的表型以及那些导致毛囊形态发生缺陷的表型 表现出高频循环的缺陷，我们在初步数据中报告了之间的关系 每个小组的成员，无毛和 Lefl。我们的初步数据表明，hr 启动子活性可以通过 Lefl 以 β-连环蛋白依赖性方式调节。该提案旨在证明 hr 表达受其启动子中的功能性 VDRE 调节。此外，由于我们发现了毛发周期的毛发生长初期和毛发生长中期阶段之间的分子联系，因此该提案旨在定义 Wnt 通路和无毛基因表达之间的遗传相互作用，以了解 HF 循环的分子基础。