Comparative Mouse Genomics Center

描述（摘自申请人的摘要） 这项提案的总体目标是开发小鼠模型，用于研究 环境敏感DNA修复/细胞周期的生物学功能 控制人类中发现的基因变异。 DNA的能力 修复是对致癌刺激敏感性的主要影响， 在风险评估中必须考虑遗传变异。 的概念 人群中常见的变异导致常见的遗传风险， 疾病引发了人们对识别DNA序列变异的强烈兴趣 被称为单核苷酸多态性（SNP）。 然而，功能 SNP变异与环境致癌物相关的重要性是 大部分未知。 这项建议旨在建立一个基因 作为人类功能基因组学的哺乳动物模型的工程小鼠系统， SNP变体-环境相互作用。 具体目标是：（1）整合 华盛顿大学健康科学资源，包括基因组学， 转基因技术，小鼠遗传学，生物信息学，生物统计学， 生态遗传学与环境健康，流式细胞术，全鼠正电子 发射断层扫描（PET）成像，比较病理学，和分子 DNA修复/细胞周期控制基因的遗传学，成为 产生和表征SNP突变小鼠。 2)产生SNP突变小鼠， 基因靶向技术，并表征和验证这些小鼠使用 在目标1中建立的综合基础设施资源。 3)开发新 小鼠基因组学技术，包括通过三种方法预测SNP功能， 三维，大分子蛋白质结构，和整个小鼠PET成像， 检测早期环境诱导的肿瘤发生。 4)建立 增强独特小鼠模型数据通信的电子数据库系统 和专业知识的环境健康科学界。 发展 这些小鼠模型将反映特定的人类， 多态性基因变异在一般人群中发现，并提供了一个 生物系统，以了解这些功能的重要性， 多态变体。

DESCRIPTION (Taken from the Applicant's Abstract) The overall objective of this proposal is to develop mouse models for studying the biological function of environmentally sensitive DNA repair/cell cycle control gene variants found in the human population. The capacity for DNA repair is a major influence in the sensitivity to carcinogenic stimuli, so genetic variants must be considered in risk assessment. The concept that common variants in the population contribute to genetic risk for common diseases has triggered intense interest in identifying DNA sequence variants known as single nucleotide polymorphisms (SNPs). However, the functional significance of SNP variants in relation to environmental carcinogens is largely unknown. This proposal is designed to establish a genetically engineered mouse system as a mammalian model for human functional genomics and SNP variant-environment interactions. The specific aims are 1) Integrate University of Washington Health Sciences resources, including genomics, transgenic technology, mouse genetics, bioinformatics, biostatistics, ecogenetics and environmental health, flow cytometry, whole mouse positron emission tomography (PET) imaging, comparative pathology, and the molecular genetics of DNA repair/cell cycle control genes, into an infrastructure for generating and characterizing SNP mutant mice. 2) Generate SNP mutant mice by gene targeting technology, and characterize and validate these mice using the integrated infrastructure resources established in Aim l. 3) Develop new mouse genomics technology including the prediction of SNP function by three- dimensional, macromolecular protein structure, and whole mouse PET imaging to detect early, environmentally induced tumorigenesis. 4) Establish an electronic database system to enhance communication of unique mouse model data and expertise to the environmental health sciences community. The development of these mouse models will mirror specific human, environmentally responsive polymorphic gene variants found in the general population, and provide a biological system for understanding the functional significance of these polymorphic variants.