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: 8489109
• 负责人: Maranke I. Koster
• 金额: $ 31.89万
• 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/8489109
• 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.

描述（由申请人提供）：p63基因编码皮肤及其附件正常发育和稳态所需的几种转录因子。虽然p63在表皮中的作用已经得到了很好的确立，但p63在毛囊（HF）中的作用仍然很难理解。p63在HF生物学中的作用是基于对p63突变引起的外胚层发育不良患者发生毛干异常的观察而提出的。然而，导致这些毛发异常的病理机制尚未阐明。根据我们的初步研究结果，我们建议，p63功能的HF干细胞的隆起。在具体目标1中，我们将通过从基因工程小鼠的隆突干细胞中切除p63来测试这一假设。对这些小鼠的分析将确定p63是否在隆突干细胞存活、更新或活化中起作用。在人类皮肤鳞状细胞癌（SCC）中也观察到p63表达减少，SCC是一种起源于隆突干细胞的肿瘤类型。然而，这一观察结果的功能意义尚不清楚。我们的初步研究结果表明，表皮和毛囊中p63的普遍下调促进皮肤SCC的发展。在具体目标2中，我们将使用基因工程小鼠进一步确定p63丢失在皮肤SCC肿瘤发生过程中的作用。我们将确定在癌基因激活的情况下，从隆突干细胞中切除p63是否会导致皮肤肿瘤易感性增加。此外，我们将确定从已建立的肿瘤中切除p63是否会加速肿瘤进展。总的来说，这些研究将提供新的见解p63在隆突干细胞在稳态和病理条件下的作用。这些研究将对p63相关外胚层发育不良患者毛发异常的治疗以及皮肤癌患者的治疗产生影响。