Transcription regulation in the hairless pathway

无毛通路中的转录调控

• 批准号: 7229415
• 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/7229415
• 关键词: Ablation; Adult; Alopecia; Animals; Apoptosis; Appendix; Atrophic; Base Pairing; Binding; Binding Sites; Biology; Brain; Cloning; Complex; Cyst; DNA; DNA Binding Domain; Data; Defect; Dermal; Disease regression; Employee Strikes; Epithelial; Exhibits; Failure; Gene Expression; Genes; Genetic; Genetic Transcription; Growth; Hair; Hair bulb structure; Hair follicle structure; Human; Human Cloning; Inbred HRS Mice; Lead; Lesion; Link; Location; Molecular; Morphogenesis; Morphology; Mus; Mutant Strains Mice; Mutation; Nuclear Receptors; Online Mendelian Inheritance In Man; Pathology; Pathway interactions; Phase; Phenotype; Plant Roots; Play; Principal Investigator; Proteins; RXR; Rattus; Regulation; Regulatory Pathway; Reporting; Research; Response Elements; Rest; Role; Sebum; Skin; Staging; Structure; Suggestion; Thinking; Thyroid Hormone Receptor; Thyroid Hormones; Transcriptional Regulation; Utricle structure; Vitamin D3 Receptor; Zinc Fingers; base; beta catenin; keratinization; keratinocyte; loss of function; member; programs; promoter; receptor; receptor binding; response; tongue papilla

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）： 近年来，对毛囊的研究取得了很大进展 生物学HF是一个动态结构，其多个隔间经历了连续的 一轮又一轮复杂而高度同步的架构重组， 毛发周期的生长（生长期）、退化（退化期）和静止（休止期）阶段。 无毛（hr）基因突变，导致小鼠和其他动物脱发， 在人类中，伴有丘疹病变的无毛症（APL，OMIM 209500）导致细胞和 已经表征的HF结构的形态变化，但很少被 关于hr表达的调节或被hr破坏的分子机制， 突变。 无毛小鼠和维生素D小鼠的病理学惊人的相似性 受体（VDR）缺失突变小鼠的研究表明，Hr和VDR是 在毛发周期途径中功能相关。最近对hr启动子的克隆 揭示了一个假定的VDR反应元件的存在，在一个相关的位置内， 启动子 尽管突变分析已经确定了两组不同的基因， 毛发表型，导致毛囊形态发生缺陷的表型和 在HF循环中表现出缺陷，我们在我们的初步数据中报告了 每组的成员，无毛和左撇子。我们的初步数据表明， 启动子活性可以由Lefl以β-连环蛋白依赖性方式调节。该建议旨在证明hr的表达受其启动子中功能性VDRE的调控。此外，因斯我们已经发现了毛发周期的生长期和退化期阶段之间的分子联系，因此该建议旨在定义Wnt途径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。