The role of p63 in hair follicle stem cells and cancer

描述(由申请人提供)：p63基因编码几种转录因子，这些转录因子是皮肤及其附件正常发育和动态平衡所必需的。虽然p63在表皮中的作用已被证实，但p63在毛囊(HF)中的作用在很大程度上仍然难以捉摸。基于观察到p63突变导致的外胚层发育不良患者的毛干异常，已经提出了p63在HF生物学中的作用。然而，导致这些毛发异常的病理机制尚未阐明。根据我们的初步发现，我们认为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去除隆起干细胞中的p63来检验这一假设。对这些小鼠的分析将确定p63是否在隆起干细胞的存活、更新或激活中发挥作用。在人类皮肤鳞状细胞癌(SCCs)中也观察到p63表达减少，这是一种起源于隆起干细胞的肿瘤类型。然而，这一观察结果的功能意义尚不清楚。我们的初步发现表明，表皮和毛囊中p63的普遍下调有助于皮肤鳞状细胞癌的发展。在具体目标2中，我们将利用基因工程小鼠进一步确定p63缺失在皮肤鳞状细胞癌发生过程中的作用。我们将确定在癌基因激活的情况下去除隆起干细胞中的p63是否会导致皮肤肿瘤易感性增加。此外，我们将确定切除已建立的肿瘤中的p63是否会加速肿瘤的进展。总而言之，这些研究将为在体内平衡和病理条件下p63在隆起干细胞中的作用提供新的见解。这些研究将对p63相关外胚层发育不良患者的头发异常治疗以及皮肤癌患者的治疗具有指导意义。 公共卫生相关性：在这项提案中，我们将确定p63在毛囊干细胞中的作用。由于这些干细胞的异常可能导致头发缺陷和皮肤癌，这些研究最终可能导致开发新的疗法来治愈这些疾病。

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.