Core B

核心将执行两个主要功能：我们将协助生成和分析异种移植肿瘤模型，并生成用于前列腺肿瘤发生的新型基因工程小鼠模型。异种移植肿瘤模型的生成和分析是耗时的，需要特定的技术专长。我们将提供技术援助和培训，以促进异种移植模型的使用。测试和生成更好的前列腺癌小鼠模型的一个主要瓶颈是将标准遗传模型与特定的附加突变相结合。我们将在核心中产生实验动物，从而从本计划内的各个项目中消除复杂转基因实验的大部分初始负担。这将促进这种遗传模型的使用，并将最大限度地减少由于无法获得遗传模型和缺乏资源而造成的成本和延误。具体而言，为支持该计划内三个项目的目标，我们将：1)为体内异种移植实验和肿瘤成像提供技术支持和培训。Core成员将参与异种移植实验的计划和启动，并将协助进行体内成像，包括Xenogen成像和骨转移的x射线成像。2)在小鼠中产生新的基因改变组合，以解决前列腺肿瘤发生中的作用。我们将把Rala和Ralb的新的条件突变与前列腺特异性Pten肿瘤抑制基因的缺失结合起来。此外，我们将分析一系列前列腺特异性PKN1基因，并将最有信息的基因与在前列腺中表达组成活性AKT1的转基因结合起来。3)产生Pkn1条件空等位基因靶向小鼠。Pkn1基因有针对性条件突变的胚胎干细胞将产生小鼠，Pkn1基因的前列腺特异性缺失将与Pten基因缺失突变相结合。4)将转基因前列腺肿瘤模型转移到纯FVB菌株背景。所有突变将转移到纯FVB菌株背景，以简化前列腺特异性肿瘤表型的分析。通过提供这些服务，我们将允许该项目开始使用动物模型更有效地分析前列腺癌的进展。

The Core will perform two major functions: We will assist with the generation and analysis of xenograft tumor models, and generate novel genetically engineered mouse models for prostate tumorigenesis. The generation and analysis of xenografts tumor models is time consuming and requires specific technical expertise. We will provide technical assistance and training to facilitate the use of xenograft models. A major bottle-neck in the testing and generation of better mouse models of prostate cancer is combining standard genetic models with specific additional mutations. We will generate experimental animals in the Core, thereby removing much ofthe initial burden of complex transgenic experiments from the individual Projects within this Program. This will facilitate the use of such genetic models, and will minimize cost and delays due to lack of access to genetic models and lack of resources. Specifically, in support of the Aims of the three Projects within the Program we will: 1) Provide technical support and training for in vivo xenograft experiments and tumor imaging. Members ofthe Core will be involved in the planning and initiation of xenograft experiments, and will assist with in vivo imaging, induding Xenogen imaging and X-ray imaging of metastases to bone. 2) Generate novel combinations of genetic alterations in mice to address roles in prostate tumorigenesis. We will combine novel conditional mutations in Rala and Ralb with prostate specific deletion of the Pten tumor suppressor. Additionally, we will analyze a series of prostate specific PKN1 transgenes, and combine the most informative with a transgene in which constitutively active AKT1 is expressed in the prostate. 3) Generate mice with a targeted Pkn1 conditional null allele. Mice will be generated from ES cells with a targeted conditional mutation in the Pkn1 gene, and prostate-specific deletion of Pkn1 will be combined with the Pten null mutation, 4) Transfer transgenic prostate tumor models to a pure FVB strain background. All mutations will be transferred to a pure FVB strain background to simplify the analysis of prostate specific tumor phenotypes. By providing these services, we will allow the Program to begin to analyze prostate cancer progression more effectively using animal models.