Biology and Molecular Regulation of Skin Stem Cells

皮肤干细胞的生物学和分子调控

• 批准号: 7331110
• 负责人: Isaac Brownell
• 金额: $ 5.51万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7331110
• 关键词: Aging; Alleles; Biological Assay; Brain; Cell Proliferation; Cells; Chromosome Mapping; Condition; Dermal; Dermis; Disease; Disease regression; Endothelial Cells; Epithelial; Epithelium; Erinaceidae; Gene Mutation; Gene Targeting; Genetic; Genetic Techniques; Growth; Hair follicle structure; Health; Homeostasis; Label; LacZ Genes; Maintenance; Malignant - descriptor; Malignant Neoplasms; Maps; Mediating; Mesenchyme; Molecular Biology; Multipotent Stem Cells; Mus; Natural regeneration; Neural Crest Cell; Phase; Plastics; Population; Prostate; Regulation; Relative (related person); Reporter; Role; Signal Transduction; Skin; Source; Stem cells; Structure; Tamoxifen; Techniques; Testing; Time; Tissues; Transgenic Organisms; Work; adult stem cell; base; daughter cell; human SMO protein; human disease; in vitro Assay; in vivo; keratinocyte; loss of function; melanocyte; nerve stem cell; prospective; recombinase; trait

DESCRIPTION (provided by applicant): Project Summary The hair follicle is a multi-lineage structure that continually undergoes cycles of regression and stem cell- mediated regeneration. Recently, highly-plastic multipotent stem cells have been isolated from both the follicular epithelium and associated dermal stroma. However, the in vivo identity of these cells has not been fully elucidated. The Joyner lab pioneered the technique of genetic inducible fate mapping (GIFM). This technique uses transgenic and gene-targeted mice to express inducible CreER recombinase in specific tissues. Tamoxifen is then administered at a designated time point to induce CreER and permanently activate a ubiquitous reporter allele such as Rosa26R in the CreER-expressing cells. These cells and their daughter cells will subsequently express LacZ. Using GIFM the Joyner lab has demonstrated a role for Sonic Hedgehog (Shh) signaling in the maintenance and expansion of both neural stem cells in the brain and stromal stem cells in the prostate. Based on preliminary observations, Shh regulates both epithelial and stromal stem cells in the cycling hair follicle. Here we propose to investigate the role of Shh in regulating stem cell contributions to the cycling follicle. We will use GIFM of Shh-responding and Shh-expressing cells to test for stem cell traits in these populations. We will also use lineage-specific loss of function studies to block Shh signaling in either the follicular epithelium or the dermis to gauge the relative requirement for Shh signaling in these tissues. Furthermore, we plan to use GIFM to track multiple lineage compartments in the skin to identify the origins of the multipotent skin stem cells derived by culture assays. Genetic labeling and conditional genetic mutation of cells in the skin will allow us to better characterize skin stem cells and the role of molecules, like Shh, that regulate them. This work will also bring us closer to being able to use skin stem cells in treating human disease, and defining their role in cancer and other conditions. Relevance The skin holds great promise as an easily accessible source of adult stem cells for use in the treatment of heritable, destructive and malignant conditions. To better characterize skin stem cells and the molecules that regulate them, we will genetically modify stem cells and follow their growth and maturation. This work will bring us closer to being able to use skin stem cells to treat disease/and defining their role in health, aging and ailments such as cancer.

描述（由申请人提供）：项目摘要毛囊是一种多条件结构，它不断发生回归和干细胞介导的再生周期。最近，已经从卵泡上皮和相关的皮肤基质中分离出高塑性多动细胞。但是，这些细胞的体内身份尚未完全阐明。 Joyner实验室开创了遗传诱导命运映射（GIFM）的技术。该技术使用转基因和靶向基因的小鼠在特定组织中表达可诱导的Creer重组酶。然后在指定的时间点进行他莫昔芬，以诱导CRER并永久激活无处不在的记者等位基因，例如表达Creer的细胞中的Rosa26R。这些细胞及其子细胞随后将表达LACZ。使用GIFM Joyner Lab已证明了Sonic刺猬（SHH）信号在脑中神经干细胞的维持和扩展中的作用，并扩展前列腺中的神经干细胞和基质干细胞。根据初步观察，SHH调节循环毛囊中的上皮和基质干细胞。在这里，我们建议研究SHH在调节干细胞对循环卵泡的贡献中的作用。我们将使用SHH反应和表达SHH的细胞的GIFM测试这些人群中的干细胞性状。我们还将使用谱系特定的功能研究丧失来阻止卵泡上皮或真皮中的SHH信号传导，以评估这些组织中SHH信号的相对需求。此外，我们计划使用GIFM跟踪皮肤中的多个谱系室，以识别由培养分析得出的多能皮肤干细胞的起源。细胞中细胞中细胞的遗传标记和条件遗传突变将使我们能够更好地表征皮肤干细胞和调节它们的分子（如SHH）的作用。这项工作还将使我们更接近能够在治疗人类疾病中使用皮肤干细胞，并定义其在癌症和其他疾病中的作用。相关性，皮肤具有巨大的前景，是一种易于获得的成年干细胞来源，用于治疗可遗传，破坏性和恶性状况。为了更好地表征皮肤干细胞和调节它们的分子，我们将基因修饰干细胞并遵循其生长和成熟。这项工作将使我们更接近使用皮肤干细胞来治疗疾病/定义其在健康，衰老和疾病（例如癌症）中的作用。