Molecular Basis of Epithelial Skin Cancer

上皮性皮肤癌的分子基础

• 批准号: 7579776
• 负责人: ANDRZEJ A. DLUGOSZ
• 金额: $ 28.95万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7579776
• 关键词: Acute; Address; Affect; Alleles; Animals; Basal cell carcinoma; Basaloid Carcinoma; Biology; Cell Death; Cells; Coupled; Development; Disease; Dominant-Negative Mutation; Doxycycline; Epithelial; Epithelium; Erinaceidae; Funding; Goals; Growth; Hair; Hair follicle structure; Hamartoma; Head and neck structure; Human; Knowledge; Lesion; Life; Link; Maintenance; Malignant Neoplasms; Mediating; Molecular; Molecular Analysis; Mouse Strains; Mus; Pathogenesis; Pathologic; Pathway interactions; Physiological; Play; Population; Protein Family; Proteins; Relative (related person); Research Personnel; Role; Skin; Skin Cancer; Skin Neoplasms; Stem cells; Testing; Transducers; Transgenes; Transgenic Organisms; base; gain of function mutation; human tissue; insight; keratinocyte; loss of function mutation; molecular imaging; mouse model; mutant; novel; overexpression; programs; receptor; response; smoothened signaling pathway; tool; transcription factor; tumor; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Deregulated hedgehog signaling plays a central role in the pathogenesis of basal cell carcinomas (BCCs) arising in skin, and a variety of other human cancers. The majority of BCCs harbor loss of function mutations in PTCH1, encoding a receptor for the hedgehog family of proteins, or gain of function mutations affecting the hedgehog signal transducer SMO. Both of these alterations result in constitutive hedgehog signaling, which may be sufficient for BCC development. We have shown that the transcription factor GH2 is the primary effector of physiologic hedgehog signaling, which is required for growth of hair follicle epithelium. Moreover, we have demonstrated that overexpression of GH2 in mice is sufficient for the development of follicle-derived skin tumors that faithfully mimic human BCCs, implicating Gli2 in pathologic hedgehog signaling associated with tumorigenesis. We plan to use novel, conditional mouse models to gain further insight into hedgehog pathway mediated tumorigenesis in skin and elsewhere, addressing the following specific aims. 1) Identify target cells for hedgehog pathway-driven tumorigenesis in skin. Aim 2) Explore the involvement of deregulated hedgehog signaling in the pathogenesis of extracutaneous tumors. Aim 3) Assess the collective function of Gli proteins in hedgehog pathway-mediated tumorigenesis. The results of these studies will further our understanding of hedgehog pathway-associated skin cancers by determining where (progenitor cell population), when (relative to the hair growth cycle), and how (downstream effectors) these tumors develop. These fundamental insights into BCC biology will add considerably to our knowledge of hedgehog pathway-associated cancer development. Moreover, the robust mouse models we are generating will provide an invaluable set of tools for further exploring the roles of hedgehog signaling in normal biology and disease.

描述(由申请人提供)：非调控的Hedgehog信号在皮肤基底细胞癌(BCC)和其他各种人类癌症的发病机制中发挥核心作用。大多数BCC含有编码Hedgehog蛋白家族受体的ptch1功能突变，或影响Hedgehog信号转导SMO的功能突变的获得。这两个改变都导致了结构性的Hedgehog信号，这可能足以促进BCC的发展。我们已经证明，转录因子GH2是生理性刺猬信号的主要效应者，这是毛囊上皮生长所必需的。此外，我们已经证明，GH2在小鼠中的过表达足以导致毛囊来源的皮肤肿瘤的发展，这种肿瘤忠实地模仿人类的基底细胞，暗示Gli2参与了与肿瘤发生相关的病理刺激性信号。我们计划使用新颖的、有条件的小鼠模型来进一步了解Hedgehog通路介导的皮肤和其他地方的肿瘤发生，解决以下具体目标。1)确定Hedgehog途径驱动的皮肤肿瘤发生的靶细胞。目的2)探讨去调节的Hedgehog信号在皮外肿瘤发病机制中的作用。目的3)探讨Gli蛋白在Hedgehog途径介导的肿瘤发生中的集体作用。这些研究的结果将通过确定这些肿瘤在哪里(祖细胞数量)、何时(相对于毛发生长周期)以及如何(下游效应因子)发展，从而加深我们对刺猬途径相关皮肤癌的理解。这些对基底细胞癌生物学的基本见解将大大增加我们对刺猬途径相关癌症发展的了解。此外，我们正在生成的健壮的小鼠模型将为进一步探索刺猬信号在正常生物学和疾病中的作用提供一套宝贵的工具。