Comparative Mouse Genomics Centers Consortiun

描述（来自申请人？s摘要） 本申请提出了生产和分析已经被免疫的小鼠。 工程化以表达细胞周期调节基因的减毒等位基因。它 预期这样的等位基因存在于人类群体中，但表现为 主要是在环境挑战之后。细胞周期调控基因 将被靶向的是细胞周期蛋白D/Cdk 4，Rb， P14 ink 6复合物，其在细胞通过 细胞周期的G1期。最初的重点将给予细胞周期蛋白D1 已知易患遗传性非息肉病的多态性 结直肠癌（HNPCC）。该项目将由Knudsen博士指导， 是Rb和细胞周期蛋白D/Cdk 4复合物的生物学专家。第二 该项目将由Yolanda Sanchez博士指导，重点关注G2检查站 和细胞周期调控基因Chk 1。桑切斯医生的专长是酵母 遗传学以及控制细胞通过G2期转运的机制 M阶段。Stambrook博士是这项研究的主要研究员， 将指导第三个项目，该项目将产生具有减毒等位基因的小鼠， 波罗激酶Plk 3。该激酶与Chkl一样，具有G2/M调节功能， 并且对DNA损伤有反应。辛辛那提大学学院 医学已承诺提供机构核心设施，其中包括 小鼠转基因核心和小鼠敲除核心。这个核心是建立在 由汤姆·多奇曼博士指导，他在这项提案中发挥了关键作用。 其他已建立的核心包括DNA合成和测序核心， 由乔安娜格罗登博士，我们的内部咨询委员会的成员， 由Greg Boivin博士指导的比较病理学核心，以及生物统计学 核心三个新的综合核心部分由霍华德休斯公司资助 医学院，医学院院长，还有孩子们？S 医院研究基金会，是可用的。其中包括DNA微阵列 核心、蛋白质组学核心和生物信息学核心。本申请提出 利用这些核心设施， 调查人员的专业知识，以进一步了解 环境挑战与细胞周期基因变异之间的相互作用 疾病的起源

DESCRIPTION (Taken from the Applicant?s Abstract) This application proposes to produce and analyze mice that have been engineered to express attenuated alleles of cell cycle regulatory genes. It is anticipated that such alleles exist in human populations, but manifest predominantly after environmental challenge. The cell cycle regulatory genes that will be targeted are those encoding members of the Cyclin D/Cdk4, Rb, P14ink6 complex, which plays a critical role in the passage of cells through the G1 phase of the cell cycle. Initial emphasis will be given to a cyclin D1 polymorphism that is known to predispose to hereditary non-polyposis colorectal cancer (HNPCC). This project will be directed by Dr. Knudsen who is expert in the biology of Rb and the Cyclin D/Cdk4 complex. A second project, to be directed by Dr. Yolanda Sanchez, focuses on the G2 checkpoint and the cell cycle regulatory gene, Chkl. Dr. Sanchez?s expertise is in yeast genetics as well as in the mechanisms governing transit of cells through G2 and M phases. Dr. Stambrook is the principal investigator of this grant and will direct a third project that will produce mice with attenuated alleles of the Polo kinase, Plk3. This kinase, like Chkl, has G2/M regulatory function and is responsive to DNA damage. The University of Cincinnati College of Medicine has made commitments to institutional core facilities, which include a mouse Transgenic Core and a mouse knockout core. This core was established and is directed by Dr. Tom Doetschman, who plays a key role in this proposal. Other established cores include a DNA synthesis and sequencing core directed by Dr. Joanna Groden, a member of our internal advisory committee, a comparative pathology core directed by Dr. Greg Boivin, and a biostatistics core. Three new integrated cores funded, in part, by the Howard Hughes Medical Institute, by the Dean of the medical school, and by the Children?s Hospital Research Foundation, are available. These include a DNA microarray core, a proteomics core, and a bioinformatics core. This application proposes to take advantage of these core facilities and to contribute the collective expertise of the investigators in furthering the understanding of the interactions between environmental challenge and variant cell cycle genes in the genesis of disease.