The role of p63 in hair follicle stem cells and cancer

p63 在毛囊干细胞和癌症中的作用

• 批准号: 8163536
• 负责人: Maranke I. Koster
• 金额: $ 33.47万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-21 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8163536
• 关键词: Ablation; Affect; Biology; Cell Survival; Cell physiology; Characteristics; Defect; Development; Disease; Down-Regulation; Ectodermal Dysplasia; Epidermis; Event; Gene Expression; Genes; Genetic; Genetically Engineered Mouse; Hair; Hair Removal; Hair follicle structure; Hair shaft structure; Homeostasis; Human; Inborn Genetic Diseases; Inherited; Lead; Mediating; Molecular; Mus; Mutation; Oncogene Activation; Oncogenic; Pathway interactions; Patients; Play; Predisposition; Process; Protein Isoforms; Regulation; Role; Skin; Skin Cancer; Skin Neoplasms; Staging; Stem cells; Testing; appendage; base; cancer stem cell; cell type; gene function; in vivo; insight; mutant; novel; skin disorder; skin squamous cell carcinoma; stem cell division; transcription factor; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The p63 gene encodes several transcription factors that are required for normal development and homeostasis of the skin and its appendages. Although the role for p63 in the epidermis has been well-established, the role for p63 in hair follicles (HF) has remained largely elusive. A role for p63 in HF biology has been suggested based on the observation that hair shaft abnormalities develop in patients with ectodermal dysplasias caused by p63 mutations. However, the pathological mechanisms that lead to these hair abnormalities have not been elucidated. Based on our preliminary findings, we propose that p63 functions in HF stem cells of the bulge. In Specific Aim 1, we will test this hypothesis by ablating p63 from bulge stem cells in genetically engineered mice. Analysis of these mice will define whether p63 functions in bulge stem cell survival, renewal, or activation. Reduced p63 expression has also been observed in human skin squamous cell carcinomas (SCCs), a tumor type that originates from bulge stem cells. However, the functional significance of this observation is not known. Our preliminary findings indicate that a general downregulation of p63 in the epidermis and hair follicles facilitates skin SCC development. In Specific Aim 2, we will further define the role of p63 loss during skin SCC tumorigenesis using genetically engineered mice. We will determine whether ablating p63 from bulge stem cells, in the presence of oncogene activation, results in increased skin tumor susceptibility. Further, we will determine whether ablating p63 from established tumors leads to accelerated tumor progression. Collectively, these studies will provide novel insights into the role of p63 in bulge stem cells under homeostatic and pathological conditions. These studies will have implications for the treatment of hair abnormalities in patients with p63-related ectodermal dysplasias as well as for the treatment of patients with skin cancer. PUBLIC HEALTH RELEVANCE: In this proposal, we will determine the role of p63 in stem cells of the hair follicle. Because abnormalities in these stem cells can cause hair defects and skin cancer, these studies may ultimately lead to the development of new therapies to cure these diseases.

描述（由申请人提供）：p63基因编码了正常发育和皮肤稳态所需的几种转录因子及其附属物。尽管p63在表皮中的作用已经建立了良好，但p63在毛囊（HF）中的作用基本上仍然难以捉摸。根据p63突变引起的外胚性异常发育不良患者的脱发异常，p63在HF生物学中的作用已提出。但是，尚未阐明导致这些头发异常的病理机制。根据我们的初步发现，我们提出p63在凸起的HF干细胞中起作用。在特定的目标1中，我们将通过在基因工程小鼠中从凸起的干细胞中消除p63的p63来检验这一假设。对这些小鼠的分析将定义p63是否在凸起的干细胞存活，更新或激活中起作用。在人类皮肤鳞状细胞癌（SCC）中也观察到p63表达降低，这是一种肿瘤类型，起源于凸起的干细胞。但是，该观察结果的功能意义尚不清楚。我们的初步发现表明，表皮和毛囊中p63的总体下调促进了皮肤SCC的发育。在特定的目标2中，我们将进一步定义使用基因工程小鼠在皮肤SCC肿瘤发生过程中p63损失的作用。我们将确定在存在癌基因激活的情况下，从凸起干细胞中消除p63是否会导致皮肤肿瘤易感性提高。此外，我们将确定从已建立的肿瘤中消除p63是否导致肿瘤进展。总的来说，这些研究将提供有关p63在稳态和病理条件下凸起干细胞中作用的新见解。这些研究将对治疗p63相关外胚性发育不良的患者的头发异常以及对皮肤癌患者的治疗。 公共卫生相关性：在此提案中，我们将确定p63在毛囊干细胞中的作用。由于这些干细胞异常会导致头发缺陷和皮肤癌，因此这些研究最终可能导致新疗法的发展来治愈这些疾病。