Mouse Model of Cell Cycle Deregulation in Cancer

描述(摘自申请人的摘要) 随着人类基因组序列即将完成，科学家们现在 面临着发现每一个人的生物功能的艰巨任务 基因和微小变异或多态的结果，使 每个人都不同于另一个人。因为这些序列变异是 一旦确定，它们无疑将与人类疾病有关，包括 因接触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非常强大的工具 在整个有机体的背景下的变体。中建议的鼠标模型 这一应用将集中在与细胞周期有关的基因和基因变体上 监管和DNA损伤检查站控制。标准转基因和 淘汰型技术，以及新的有条件和可诱导的技术， 将被用来开发这些模型。这些鼠标模型将是 以组织病理学和分子水平为特征及其反应 对致癌物质，包括化学和紫外线辐射，都将进行分析。新的 功能基因组技术将被用于进行深入的分析 在这些小鼠模型中发生的基因表达的变化 特定的基因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器官系统的模型上。 然而，由于转基因和靶向构建物的性质， 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、 胆汁和上呼吸道。这组调查人员已经 转基因小鼠开发、分子生物学方面的专业知识(特别是 它与细胞周期、病理学、小鼠遗传学、癌症发生、 生物统计学和功能基因组学。高级调查员已经 在鼠标皮肤系统方面有经验，之前曾合作过 建立和鉴定转基因小鼠模型。世界卫生组织的科学目标 拟进行的研究如下：1)生物学特性 细胞周期蛋白D1的变种，2)E2F1抑制的机制 肿瘤发生，3)BRCA1和PTEN的正常调节功能 上皮组织动态平衡，以及4)人类p21基因多态的作用 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有望 适用于附加鼠标的开发和表征 基于人类基因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.