Cellular and Transgenic Phenotyping Core

细胞和转基因表型核心将提供面向服务的资源以及正在进行的 确保项目效率和生产率的技术开发和优化 研究人员对候选胰腺癌序列进行功能评估。这将是 通过集中和标准化使用体外、基于细胞的分析以及 详细评估小鼠、斑马鱼和异种移植模型的体内表型。老鼠是一口井- 特色化的哺乳动物模型系统，具有广泛的遗传工具箱，可用于 产生原发肿瘤的操作，免疫缺陷菌株促进体内直接 作为异种移植的人类癌细胞的分析，以及与人类癌症生物学和 治疗学。斑马鱼是一种新兴的癌症遗传学模型和发育模型 高效，允许高通量的活体脊椎动物基因筛查，并可以有效地分析，因为 成熟时体积较小，发育期间光学清晰度较高。核心A将为以下客户提供集中服务 根据标准化标准对这些模型的有效使用和组织学分析。具体的 目标是：目标1)提供组织病理学解释、组织增殖分析和基因 由项目1、2、3和4提供的小鼠和斑马鱼组织的路径评估；和目标2)应用 并改进免疫缺陷小鼠的异位和原位异种移植模型，用于体内评估 包括基因或microRNA序列在内的胰腺癌候选序列的体内功能 项目2、3和4的致瘤性、肿瘤生长、间质发展和转移分析。 相关性(请参阅说明)： 胰腺癌相关基因和microRNA的功能特征将导致 发现治疗胰腺癌的新靶点，这是迫切需要的。斑马鱼 而这项提案中所描述的老鼠模型在未来也将成为验证和 在将新疗法投入人体临床试验之前，对这些新疗法进行安全性测试。

The Cellular and Transgenic Phenotyping Core will provide a service-oriented resource along with ongoing technique development and optimization that will ensure the efficiency and productivity of project investigators in the functional evaluation of candidate pancreatic cancer sequences. This will be accomplished through the centralized and standardized use of both in vitro, cell based assays as well as detailed assessment of in vivo phenotypes in mouse, zebrafish, and xenograft models. The mouse is a well- characterized mammalian model system with an extensive genetic toolbox available for genetic manipulations to generate autochthonous tumors, immunodeficient strains that facilitate direct in vivo analysis of human cancer cells as xenografts, and a track record of relevance to human cancer biology and therapeutics. Zebrafish are an emerging cancer genetics model and developmental model that arecost efficient, permit high throughput in vivo vertebrate genetic screens, and can be efficiently analyzed due to their small size at maturity and optical clarity during development. Core A will provide centralized services for the efficient use and histological analysis of these models according to standardized criteria. The Specific Aims are: Aim 1) to provide histopathology interpretation, histological proliferation analysis, and gene pathway evaluation of mouse and zebrafish tissues supplied by Projects 1,2,3, and 4; and Aim 2) to apply and refine ectopic and orthotopic xenograft models in immunodeficient mice for in vivo evaluation of the function of candidate pancreatic cancer sequences including genes or microRNA sequences using in vivo tumorigenicity, tumor growth, stromal development, and metastasis assays for Projects 2,3, and 4. RELEVANCE (Seeinstructions): Functional characterizationof the genes and microRNA'sinvolved in pancreatic cancer will lead to the discovery of new targets for treatment of pancreatic cancer which are desperately needed. The zebrafish and mouse models characterized in this proposal will in the future also serve as ideal tools for validation and safety testing of these new treatments before moving the new therapies into human clinical trials.