Genetic Regulators of Human Melanocytic Neoplasia

人类黑素细胞肿瘤的遗传调节因子

• 批准号: 7090072
• 负责人: AMY E ADAMS
• 金额: $ 11.85万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7090072
• 关键词: SCID mouse; biological signal transduction; cadherins; cell adhesion; clinical research; disease /disorder model; gene induction /repression; genetic regulation; genetically modified animals; guanine nucleotide binding protein; human tissue; laboratory mouse; melanocyte; melanoma; neoplasm /cancer invasiveness; p53 gene /protein; protein structure function; transcription factor; SCID mouse; biological signal transduction; cadherins; cell adhesion; clinical research; disease /disorder model; gene induction /repression; genetic regulation; genetically modified animals; guanine nucleotide binding protein; human tissue; laboratory mouse; melanocyte; melanoma; neoplasm /cancer invasiveness; p53 gene /protein; protein structure function; transcription factor

DESCRIPTION (provided by applicant): Genetic Regulators of Human Melanocytic Neoplasia: Malignant melanoma is the most common fatal skin cancer. Human tumor samples and mouse models have provided insight into pathways that are altered in melanoma, including activation of Ras, blockade of Rb and p53, as well as change n the adhesion molecule repertoire. However, the medical relevance of murine models of melanoma is limited by major differences between mouse and human skin architecture and by the greater ease of transformation of murine cells. No study has yet addressed the necessity of specific genetic elements in the promotion or maintenance of melanoma in human tissue. Our laboratory's recent finding that defined genetic elements (namely activated Ras, dominant-negative p53, activated cdk4) can act in concert to recapitulate invasive human rnelanocytic neoplasia in human skin regenerated on immune-deficient mice allows for studies of the mechanistic basis for human rnelanocytic carcinogen sis. This proposal aims to use this model to determine the role of specific regulatory proteins and adhesion molecules in the promotion of human rnelanocytic neoplasia. First, the role of the Ras downstream regulator B-Raf will be examined by evaluating the effects of a) activated B-Raf mutants and b) the blockade of downstream Ras effectors on the induction of invasive rnelanocytic neoplasia in primary melanocytes in reconstituted human skin. Second we will address the role of the order of genetic alterations in tumor induction using reciprocal temporal induction of dominant-negative p53 and activated Ras. Additionally, we will determine if p53 disruption is necessary/ to sustain rnelanocytic neoplasia. Third, we will use both genetic and biochemical means to modify E- and N-cadheriri activity, to determine their role in tumor invasion. These studies will provide greater understanding of the roles of Ras, p53, and cadherins in the pathogenesis of rnelanocytic tumors, and may provide targets for therapeutic intervention in human melanoma.

描述（由申请人提供）： 人黑色素细胞肿瘤的遗传调节剂：恶性黑色素瘤是最常见的致命皮肤癌。人类肿瘤样品和小鼠模型已提供了对黑色素瘤改变的途径的见解，包括RAS的激活，RB和p53的封锁，以及改变粘附分子库。然而，黑色素瘤鼠模型的医学相关性受小鼠和人皮肤结构之间的主要差异以及鼠细胞转化的易于变化的限制。尚无研究涉及在人体组织中促进或维持黑色素瘤中特定遗传因素的必要性。我们的实验室最近的发现，即定义的遗传元件（即激活的RA，主导的阴性p53，激活的CDK4）可以协同起作用，以概括人类皮肤中人类皮肤上的侵袭性人类r型肿瘤性肿瘤性肿瘤，从而可以在免疫缺陷型中重新生成，从而可以研究人类rnelanoanocytic carccycy carccycy carccyin carcciyen carccyin siss siss sis。该建议旨在使用该模型来确定特定调节蛋白和粘附分子在促进人雷诺型肿瘤中的作用。首先，将通过评估a）激活的B-RAF突变体的作用来研究RAS下游调节剂B-RAF的作用，b）下游RAS效应子对诱导侵入性肾素瘤的封锁，在重构人类皮肤中诱导侵袭性的r型肿瘤性肿瘤。其次，我们将利用互惠的p53和活化的Ras来解决遗传改变在肿瘤诱导中的作用。此外，我们将确定p53的破坏是否需要/维持rne型肿瘤。第三，我们将同时使用遗传和生化手段来修饰E-和N-钙卫纤维活性，以确定它们在肿瘤侵袭中的作用。这些研究将对RAS，p53和钙粘蛋白在rneanocyty肿瘤发病机理中的作用有更深入的了解，并可能为人类黑色素瘤的治疗干预提供靶标。