Regulation of skin epithelial stem cell homeostasis

皮肤上皮干细胞稳态的调节

• 批准号: 7991686
• 负责人: Hoang Nguyen
• 金额: $ 34.54万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7991686
• 关键词: Ablation; Adult; Affect; Binding; Biological Assay; Cancerous; Cell Death; Cell physiology; Cells; Characteristics; Data; Defect; Development; Disease; Embryo; Embryonic Development; Epidermis; Epithelial; Epithelium; Equilibrium; Future; Gene Targeting; Genes; Genetic; Genetic Transcription; Goals; Hair; Hair follicle structure; Homeostasis; In Vitro; Knowledge; Life; Ligands; Light; Maintenance; Malignant Neoplasms; Mediating; Mediator of activation protein; Microarray Analysis; Molecular; Morphogenesis; Mus; Mutation; Natural regeneration; Nuclear Translocation; Null Lymphocytes; Play; Process; Regenerative Medicine; Regulation; Role; Sebaceous Glands; Signal Pathway; Signal Transduction; Skin; Stem cells; System; Tamoxifen; Testing; Tissues; Work; appendage; base; cancer cell; cell growth; epidermis cell; genome-wide; in vivo; interest; keratinocyte; member; migration; mouse model; pluripotency; postnatal; public health relevance; self-renewal; skin regeneration; stem cell biology; stem cell population; transcription factor; tumorigenesis

DESCRIPTION (provided by applicant): Tissue morphogenesis and homeostasis require proper stem cell (SC) function. Our long-term goal is to understand the molecular mechanisms that underlie how SCs self-renew, maintain their multipotent state, and differentiate into multiple lineages. This knowledge of SC biology is important to better manipulate SCs for uses in regenerative medicine, and to understand how their aberrations might contribute to a variety of diseases including tumorigenesis. 2-catenin is the key mediator of the canonical Wnt signaling pathway, which controls many aspects of development, including SC activation during hair morphogenesis and regeneration. Tcf3 and Tcf4 are HMG transcription factor members that either can activate gene transcription when bound to 2-catenin, or can repress target gene transcription when bound to corepressors. However, it remains unclear whether, in the absence of 2-catenin, Tcf3/4 repress only Wnt target genes or whether Tcf3/4 also function to repress genes that are independent of the Wnt/2-catenin signaling pathway. Tcf3 has been shown to be one of the core components of the regulatory network of embryonic SCs, and its expression in other adult SCs suggests that it likely plays an important role in these SCs as well. Our preliminary results show that Tcf3/4 loss affects skin epithelial stem cell homeostasis. In this proposal we aim to determine the Wnt-dependent and Wnt-independent function of Tcf3 and Tcf4 in maintaining skin epithelial stem cell homeostasis. We employ a genetic mouse model with targeted Tcf3/4 genes to dissect the mechanisms by which Tcf3/4 regulate stem cells homeostasis, using both in vitro and in vivo assays. This will allow us to delineate the Wnt/2-catenin dependent and independent role of Tcf3/4 in controlling specific function that allow epidermal stem cells homeostasis. PUBLIC HEALTH RELEVANCE: Understanding how stem cells grow and are controlled is of tremendous interest because of the potential use of stem cells for tissue replacement. In addition, it is also important for our understanding of cancer since cancer cells often display many characteristics of stem cells, as recent evidence suggests that cancerous cells might arise from stem cell origin. In this proposal we propose to determine how the loss of two particular genes disrupts the maintenance of skin epithelial stem cells and identify the mechanism by which they control their fate.

描述(由申请人提供)： 组织形态发生和动态平衡需要适当的干细胞(SC)功能。我们的长期目标是了解干细胞自我更新、维持其多潜能状态以及分化为多个谱系的分子机制。对干细胞生物学的了解对于更好地操纵干细胞用于再生医学，以及了解它们的异常如何可能导致包括肿瘤发生在内的各种疾病是重要的。2-连环蛋白是典型的Wnt信号通路的关键介质，它控制着许多方面的发育，包括毛发形态发生和再生过程中SC的激活。TCF3和TCF4是HMG转录因子成员，既可以在与2-连环蛋白结合时激活基因转录，也可以在与辅阻遏子结合时抑制靶基因转录。然而，目前尚不清楚在缺乏2-catenin的情况下，Tcf3/4是否只抑制Wnt靶基因，或者Tcf3/4是否也发挥功能抑制不依赖于Wnt/2-catenin信号通路的基因。TCF3已被证明是胚胎干细胞调控网络的核心组成部分之一，它在其他成年干细胞中的表达表明，它可能也在这些干细胞中发挥着重要作用。我们的初步结果表明，Tcf3/4的缺失会影响皮肤上皮干细胞的动态平衡。在这项建议中，我们的目标是确定Tcf3和TCF4在维持皮肤上皮干细胞动态平衡中的Wnt依赖和Wnt非依赖功能。我们利用带有靶向Tcf3/4基因的小鼠遗传模型，通过体外和体内分析来剖析Tcf3/4调节干细胞动态平衡的机制。这将使我们能够描述Wnt/2-catenin依赖和独立的Tcf3/4在控制允许表皮干细胞动态平衡的特定功能中的作用。 公共卫生相关性： 了解干细胞是如何生长和控制的是非常有意义的，因为干细胞有可能用于组织替代。此外，这对于我们对癌症的理解也很重要，因为癌症细胞经常表现出干细胞的许多特征，因为最近的证据表明，癌细胞可能来自干细胞来源。在这项建议中，我们建议确定两个特定基因的丢失如何扰乱皮肤上皮干细胞的维持，并确定它们控制其命运的机制。