Genetic Pathways of Hair Medulla Differentiation-Paradigms for Development

毛髓分化的遗传途径-发育范例

• 批准号: 7230136
• 负责人: ALEXANDER AWGULEWITSCH
• 金额: $ 16.82万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2008-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7230136
• 关键词: AKR/J Mouse; Address; Affect; Attention; Binding; Biological Assay; Biology; Chromosomes, Human, Pair 1; Complex; Condition; Critical Pathways; Data; Defect; Development; Disease; Distal; Fiber; Figs - dietary; Future; Genes; Genetic; Hair; Hair follicle structure; Health; In Situ Hybridization; In Vitro; Inbred Mouse; Individual; Light; Link; Localized; Maps; Methods; Modeling; Molecular; Molecular Biology; Morphogenesis; Mus; Mutant Strains Mice; Mutate; Mutation; Northern Blotting; Numbers; Pathway interactions; Pattern; Phenotype; Pilum; Play; Polymerase Chain Reaction; Process; Protein Overexpression; Regulation; Regulator Genes; Regulatory Pathway; Reporter Genes; Resolution; Role; Sampling; Screening procedure; Series; Single Nucleotide Polymorphism; Skin; Structural Genes; Structure; Testing; Time; Tissues; Transgenic Mice; Trichothiodystrophy; base; body system; human disease; insight; mRNA Expression; mutant; novel; postnatal; simple sequence length polymorphism

DESCRIPTION (provided by applicant): Skin and hair are obvious external features that directly reflect an individuals' health condition. Genes that regulate normal development and function of the skin often play critical roles in other organ systems. While there is much focus on skin and hair follicle cycling and development, very little is known about the formation of the hair medulla. We recently determined that the transcriptional regulator Hoxc13 plays a key role in hair follicle differentiation, including the formation of the medulla, where it is involved in the control of other regulatory genes (Foxql, Foxnl, Junb), as well as structural genes (Crispl, Krt2-16, Dsc2). All of these genes have been implicated in a host of abnormalities in tissues other than hair. Our overall hypothesis is that using the hair follicle medulla as a model for defining functional regulatory networks including these genes will be of great relevance for understanding complex disease mechanisms involving mutations or dysregulation of the same genes. Aim1: We will begin by investigating the hair interior defect (hid) mutation, which affects medulla formation and appears to be linked to a novel gene. Having mapped the hid mutation recently to mouse chromosome 1, we will localize it further by high-resolution mapping to identify the corresponding gene and characterize its expression pattern. Aim2: To define the genetic pathways of medulla differentiation involving hid, a multi-step approach will utilize cross-examination of expression patterns of genes associated with medulla differentiation in a panel of corresponding hair medulla mutant mice including hid by in situ hybridization j and real-time quantitative PCR. Individual pathway predictions will be tested in subsequent steps by generating compound mutants and in vitro DMA binding assays. Dissecting the regulatory circuitry controlling hair medulla formation will significantly contribute to understanding the mechanisms underlying diseases not only of the hair and skin but of many other organ systems as well.

描述（申请人提供）：皮肤和毛发是直接反映个人健康状况的明显外部特征。调节皮肤正常发育和功能的基因通常在其他器官系统中发挥关键作用。虽然人们对皮肤和毛囊的循环和发育有很多关注，但对毛髓质的形成知之甚少。我们最近确定转录调节因子Hoxc 13在毛囊分化中起关键作用，包括髓质的形成，其中它参与控制其他调节基因（Foxql，Foxnl，Junb）以及结构基因（Crispl，Krt 2 -16，Dsc 2）。所有这些基因都与头发以外的组织中的许多异常有关。我们的总体假设是，使用毛囊髓质作为一个模型，用于定义功能的调控网络，包括这些基因将是非常相关的理解复杂的疾病机制，涉及突变或失调的相同的基因。目标1：我们将开始调查头发内部缺陷（hid）突变，它影响骨髓的形成，似乎与一个新的基因。在定位了小鼠1号染色体上的隐藏突变后，我们将通过高分辨率定位进一步定位它，以确定相应的基因并表征其表达模式。目标2：为了确定涉及HID的髓质分化的遗传途径，多步骤方法将利用原位杂交和实时定量PCR交叉检查一组相应的毛髓质突变小鼠（包括HID）中与髓质分化相关的基因的表达模式。在后续步骤中，将通过生成化合物突变体和体外DMA结合试验对单个途径预测进行测试。解剖控制毛髓质形成的调节回路将大大有助于理解不仅是头发和皮肤，而且是许多其他器官系统的疾病的潜在机制。