Comparative Mouse Genomics Center

描述(摘自申请人的摘要) 这项建议的总体目标是开发用于研究的小鼠模型 环境敏感的DNA修复/细胞周期的生物学功能 控制在人类群体中发现的基因变异。DNA的容量 修复是对致癌刺激敏感性的主要影响因素，因此 在风险评估中必须考虑遗传变异。这个概念就是 人群中常见的变异会导致共同的遗传风险 疾病引发了人们对识别DNA序列变异的浓厚兴趣 称为单核苷酸多态(SNPs)。然而，功能性的 SNP变异与环境致癌物质的关系的意义是 很大程度上是未知的。这项提议旨在建立一种基因上的 作为人类功能基因组学哺乳动物模型的工程化小鼠系统 SNP变异与环境的相互作用。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，为 培育和鉴定SNP突变小鼠。2)通过以下方式获得SNP突变小鼠 基因打靶技术，并使用 在AIM建立综合基础设施资源L。3)开发新的 小鼠基因组学技术包括SNP功能的预测 维度、大分子蛋白质结构和整个小鼠PET成像 发现早期的、环境诱导的肿瘤形成。4)建立 电子数据库系统，以加强独特鼠标模型数据的交流 并向环境健康科学界提供专业知识。最新进展 这些老鼠模型将反映特定的人类，对环境有反应 在普通人群中发现的多态基因变异，并提供了一种 了解这些蛋白功能意义的生物学系统 多态的变种。

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.