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，在理解毛囊（HF）方面取得了很多进展 生物学。 HF是一种动态结构，其多个隔室连续 在此期间的复杂且高度同步的建筑重组 生长（Anagen），回归（catagen）和静止（端基）阶段。 无毛（HR）基因的突变，引起小鼠和其他动物的脱发，以及 人类中丘疹病变（APL，OMIM 209500）的纹理，导致细胞和 形态学的HF结构变化已被表征，但几乎没有 知道HR表达的调节或H r破坏的分子机制 突变。 无毛小鼠和维生素D的病理学的惊人相似性 受体（VDR）无突变小鼠已提出了这样的建议，即HR和VDR是 在头发周期路径中功能相关。人力资源启动子的最近克隆具有 揭示了在相关位置中存在假定的VDR响应元件 发起人。 尽管突变分析已经确定了两种导致的基因 头发表型，那些导致卵泡形态发生缺陷的表型以及 在HF循环中表现出缺陷，我们在初步数据中报告 每个小组的成员，无毛和Lefl。我们的初步数据表明 LEFL可以以β-catenin的依赖性方式调节启动子活性。该建议旨在证明HR表达受功能Vdrein的启动子的调节。此外，INCE我们已经发现了头发周期的Anagen和Catagen阶段之间的分子联系，该建议旨在定义Wnt途径与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。