MOUSE MODELS FOR PROSTATE CARCINOGENESIS

前列腺癌是世界上最常见的男性癌症。 美国，是一个重大的公共卫生问题。 的 前列腺增生发生和发展的分子事件 致癌作用未知。 我们认为p53和视网膜母细胞瘤 (Rb)肿瘤抑制基因是前列腺中两个关键的遗传靶点 肿瘤发展 此外，我们建议， 肿瘤的发展也受到以下因素的协同作用的控制： 特异性激活的癌基因和肿瘤抑制基因的功能。 在以下具体目的中，我们将使用一种新的动物模型系统 为了阐明p53、Rb和其他基因在多步骤过程中的作用， 前列腺癌的发生：（一）表征和优化 用于靶向表达的基于C3（1）的前列腺表达载体 前列腺中的转基因，（ii）构建转基因 表达与人类前列腺癌有关的基因的小鼠系，或 已知直接影响这些基因功能的基因，（iii） 分析转基因对前列腺生长的影响， 开发，和（iv）开发用于 雄激素调节的转基因表达。 实验方法建立在我们成功的设计和 基于充分表征的表达载体的实施 大鼠C3（1）类固醇结合蛋白基因。 转基因小鼠品系已经被 产生的β-半乳糖苷酶（β-gal）和人类 乳头瘤病毒16型E6和E7基因在转录控制下 C3（1）调节元件。 选择C3（1）基因作为基础 对于我们的表达载体系统来说，因为基因的转录 局限于前列腺的腹叶 该提案概述了一套利用转基因技术的创新方法， 小鼠技术，以解决特定细胞基因的作用， 前列腺肿瘤的发病机制。 这一长期目标 建议是鉴定参与起始的其他基因， 前列腺癌的进展和转移，并设计策略 以及用于检测和治疗这种疾病的疗法。

Carcinoma of the prostate is the most prevalent cancer in males in the United States and represents a major public health concern. The molecular events underlying the initiation and progression of prostate carcinogenesis are unknown. We propose that the p53 and retinoblastoma (Rb) tumor suppressor genes are two pivotal genetic targets in prostate neoplastic development. In addition, we propose that the course of neoplastic development is also governed by the synergistic effects of specific activated oncogenes and the tumor suppressor gene functions. In the following Specific Aims we will use a novel animal model system to address the roles of p53, Rb, and other genes in the multistep process of prostate carcinogenesis by: (i) characterization and optimization of the C3(1)-based prostate expression vector for the targeted expression of transgenes in the prostate gland, (ii) construction of transgenic mouse lines that express genes implicated in human prostate cancer, or genes known to directly affect the function of these genes, (iii) analysis of the effects of the transgenes on prostate growth and development, and (iv) development of a binary transgenic system for androgen-regulated expression of transgenes. The experimental methodology builds on our successful design and implementation of an expression vector based on the well-characterized rat C3(1) steroid binding protein gene. Transgenic mouse lines have been generated with the Beta-galactosidase (Beta-gal) and the human papillomavirus type 16 E6 and E7 genes under transcriptional control of the C3(1) regulatory elements. The C3(1) gene was chosen as the basis for our expression vector system because transcription of the gene is restricted to the ventral lobe of the prostate. This proposal outlines a set of innovative approaches using transgenic mouse technologies to address the roles of specific cellular genes in the pathogenesis of prostate neoplasia. The long term objectives of this proposal are to identify additional genes involved in the initiation, progression, and metastasis of prostate cancer and to design strategies and therapies for the detection and treatment of this disease.