Mouse Model of Cell Cycle Deregulation in Cancer

描述（摘自申请人的摘要） 随着人类基因组测序的即将完成，科学家们现在 面临着发现每一种生物功能的艰巨任务， 基因和小的变化，或多态性的后果，使 一个个体不同于另一个个体。 由于这些序列变异是 一旦确定，它们无疑将与人类疾病有关，包括 由于暴露于环境因素而引起的疾病。 转基因小鼠 模型是研究基因和基因功能的有力工具 在整个生物体中的变异。 中提出的小鼠模型 这一应用将集中在与细胞周期有关的基因和基因变异上 调节和DNA损伤检查点控制。 标准转基因和 敲除技术，以及新的条件和诱导技术， 将用于开发这些模型。 这些小鼠模型将 在组织病理学和分子水平上表征， 致癌物质，包括化学和紫外线辐射，将进行分析。 新 功能基因组技术将被用于进行深入分析 在这些小鼠模型中发生的基因表达的变化 特定的遗传改变和对致癌物暴露的反应。 这些研究最初将集中在皮肤作为模型器官系统。 然而，由于转基因和靶向构建体的性质， 用于生成这些模型，也有可能研究其他 上皮组织，包括前列腺，乳腺，胸腺，膀胱， 胆囊和上呼吸消化道。 这组调查人员已经 转基因小鼠开发、分子生物学（特别是 它涉及细胞周期），病理学，小鼠遗传学，致癌作用， 生物统计学和功能基因组学。 高级调查员已经 在小鼠皮肤系统的经验，并曾在一起工作， 开发和表征转基因小鼠模型。 科学的目标， 建议的研究是确定以下内容：1）生物学特性 2）E2F1抑制细胞周期蛋白D1的机制， 3）BRCA 1和PTEN在调节肿瘤发生中的正常功能 上皮组织稳态，和4）人p2l多态性的作用， 癌症易感性的变异。 此外，转基因模型 将开发的方法和功能基因组工具将有望 适用于其他小鼠的开发和表征 基于人类遗传变异的新发现的模型。

DESCRIPTION (Taken from the Applicant's Abstract) With the imminent completion of the human genome sequence, scientists are now faced with the daunting task of discovering the biological function of each gene and the consequence of the small variations, or polymorphisms, that make one individual different from another. As these sequence variations are identified, they will undoubtedly be linked to human diseases, including diseases caused by exposure to environmental agents. Transgenic mouse models are very powerful tools for studying the function of genes and gene variants in the context of a whole organism. The proposed mouse models in this application will focus on genes and gene variants involved in cell cycle regulation and DNA damage checkpoint control. Standard transgenic and knockout technologies, as well as new conditional and inducible technologies, will be used to develop these models. These mouse models will be characterized at the histopathological and molecular levels and their response to carcinogenic agents, both chemical and UV radiation, will be analyzed. New functional genomic technologies will be used to perform an in-depth analysis of the changes in gene expression that occur in these mouse models as a result of the specific genetic alterations and in response to carcinogen exposure. The studies will initially be focused on the skin as a model organ system. However, because of the nature of the transgenes and targeting constructs to be used in generating these models, there is also the potential to study other epithelial tissues, including the prostate, mammary gland, thymus, bladder, gall bladder, and upper aerodigestive tract. This group of investigators has expertise in transgenic mouse development, molecular biology (particularly as it relates to the cell cycle), pathology, mouse genetics, carcinogenesis, biostatistics, and functional genomics. The senior investigators have experience in the mouse skin system and have previously worked together to develop and characterize transgenic mouse models. The scientific goals of the proposed studies are to determine the following: 1) the biological properties of a variant of cyclin Dl, 2) the mechanism by which E2Fl suppresses tumorigenesis, 3) the normal function of BRCA1 and PTEN in regulating epithelial tissue homeostasis, and 4) the role of a human p2l polymorphic variant in cancer susceptibility. In addition, the transgenic model approaches and functional genomic tools that will be developed will hopefully be applicable for the development and characterization of additional mouse models based on new discoveries of genetic variations in humans.