Cancer susceptibility of XRCC1 mutant mice

XRCC1突变小鼠的癌症易感性

基本信息

批准号：
7439285
负责人：
Warren C LADIGES
金额：
$ 19.5万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-08 至 2010-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The main focus of this proposal is investigation of the concept that functional variation in the DNA repair gene XRCC1 can influence susceptibility to carcinogen-induced tumorigenesis. XRCC1 has been shown to be a key player involved in base excision repair, single strand break repair, and possibly double strand break repair. A number of XRCC1 polymorphisms have been identified, and cancer association studies have received extensive epidemiological attention but with conflicting results. In order to help validate the important biological role of DNA repair and specifically XRCC1, in environmental carcinogenesis we are proposing to use mutant mouse models representing human haploinsufficiency and polymorphisms. XRCC1 has no known enzymatic activity, but depends on protein to protein interactions to carry out its functional role in DNA repair. Therefore, use of a biological system such as the mouse to help define function related to expression of an observable tumor phenotype when challenged with a carcinogen is a major means of investigating XRCC1 function. Azoxymethane (AOM) is an alkylating agent and a well-established carcinogen in mice with a spectrum of pre-tumor, pre-malignant, and malignant lesions in the colon and to a lesser extent the liver. It also serves as a prototype for alkylating agents present in the environment that present potentially significant exposure risks. Our hypothesis is that cancer susceptibility to AOM can be influenced by XRCC1 haploinsufficiency and single nucleotide polymorphisms R194W and R280H. Information generated from our proposed studies could be used to help design clinically relevant studies to identify individuals or groups that may be at increased cancer risk for specific environmental conditions. PUBLIC HEALTH RELEVANCE: The main focus of this proposal is investigation of the concept that functional variation in the DNA repair gene XRCC1 can influence susceptibility to carcinogen-induced tumorigenesis. XRCC1 has been shown to be a key player involved in base excision repair, single strand break repair, and possibly double strand break repair. A number of XRCC1 polymorphisms have been identified, and cancer association studies have received extensive epidemiological attention but with conflicting results. In order to help validate the important biological role of DNA repair and specifically XRCC1, in environmental carcinogenesis we are proposing to use mutant mouse models representing human haploinsufficiency and polymorphisms.

描述（由申请人提供）：该提案的主要焦点是研究 DNA 修复基因 XRCC1 的功能变异可以影响对致癌物诱导的肿瘤发生的易感性的概念。 XRCC1 已被证明是参与碱基切除修复、单链断裂修复以及可能的双链断裂修复的关键参与者。许多 XRCC1 多态性已被鉴定，癌症关联研究已受到流行病学的广泛关注，但结果相互矛盾。为了帮助验证 DNA 修复（特别是 XRCC1）在环境致癌中的重要生物学作用，我们建议使用代表人类单倍体不足和多态性的突变小鼠模型。 XRCC1 没有已知的酶活性，但依赖于蛋白质与蛋白质的相互作用来发挥其在 DNA 修复中的功能作用。因此，使用小鼠等生物系统来帮助定义与致癌物攻击时可观察到的肿瘤表型表达相关的功能是研究 XRCC1 功能的主要手段。氧化偶氮甲烷 (AOM) 是一种烷化剂，也是一种公认的致癌物，对患有一系列结肠癌前期、癌前病变和结肠恶性病变（较小程度的肝脏病变）的小鼠来说，它是一种公认的致癌物。它还可以作为环境中存在的存在潜在重大暴露风险的烷化剂的原型。我们的假设是，癌症对 AOM 的易感性可能受到 XRCC1 单倍体不足和单核苷酸多态性 R194W 和 R280H 的影响。我们拟议的研究产生的信息可用于帮助设计临床相关研究，以确定在特定环境条件下可能面临更高癌症风险的个人或群体。公共健康相关性：该提案的主要重点是研究 DNA 修复基因 XRCC1 的功能变异可能影响致癌物诱导的肿瘤发生的易感性这一概念。 XRCC1 已被证明是参与碱基切除修复、单链断裂修复以及可能的双链断裂修复的关键参与者。许多 XRCC1 多态性已被鉴定，癌症关联研究已受到流行病学的广泛关注，但结果相互矛盾。为了帮助验证 DNA 修复（特别是 XRCC1）在环境致癌中的重要生物学作用，我们建议使用代表人类单倍体不足和多态性的突变小鼠模型。