Regulation of skin epithelial stem cell homeostasis

皮肤上皮干细胞稳态的调节

• 批准号: 8488414
• 负责人: Hoang Nguyen
• 金额: $ 31.5万
• 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/8488414
• 关键词: Ablation; Adult; Affect; Binding; Biological Assay; Cancerous; Cell Death; Cell Survival; 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.

描述（由申请人提供）： 组织形态发生和稳态需要适当的干细胞（SC）功能。我们的长期目标是了解SC如何自我更新，维持其多能状态并分化成多个谱系的分子机制。这种SC生物学知识对于更好地操纵SC用于再生医学以及了解它们的畸变如何导致包括肿瘤发生在内的各种疾病是重要的。2-连环蛋白是经典Wnt信号通路的关键介质，其控制发育的许多方面，包括毛发形态发生和再生期间的SC活化。Tcf 3和Tcf 4是HMG转录因子成员，当与2-连环蛋白结合时可以激活基因转录，或者当与辅阻遏物结合时可以抑制靶基因转录。然而，目前尚不清楚在缺乏2-连环蛋白的情况下，Tcf 3/4是否仅抑制Wnt靶基因，或者Tcf 3/4是否也具有抑制不依赖于Wnt/2-连环蛋白信号通路的基因的功能。Tcf 3已被证明是胚胎SC调控网络的核心组成部分之一，它在其他成体SC中的表达表明它可能在这些SC中也起着重要作用。我们的初步结果表明，Tcf 3/4损失影响皮肤上皮干细胞的稳态。在这项提案中，我们的目标是确定Wnt依赖和Wnt独立的功能Tcf 3和Tcf 4在维持皮肤上皮干细胞的稳态。我们采用了一个遗传小鼠模型与靶向Tcf 3/4基因解剖Tcf 3/4调节干细胞稳态的机制，使用在体外和体内试验。这将使我们能够描述Tcf 3/4在控制允许表皮干细胞稳态的特定功能中的Wnt/2-连环蛋白依赖性和独立性作用。