Cancer susceptibility of XRCC1 mutant mice

XRCC1突变小鼠的癌症易感性

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/7439285
• 关键词: Alkylating Agents; Attention; Azoxymethane; Base Excision Repairs; Biological; Carcinogens; Colon; Condition; Conflict (Psychology); DNA Repair; DNA Repair Gene; Double Strand Break Repair; Environment; Genetic Polymorphism; Genetic Variation; Genus Cola; Human; Individual; Investigation; Lesion; Liver; Malignant - descriptor; Malignant Neoplasms; Mus; Mutant Strains Mice; Numbers; Phenotype; Predisposition; Premalignant; Proteins; Public Health; Risk; Role; Single Nucleotide Polymorphism; Single Strand Break Repair; System; Variant; XRCC1 gene; cancer risk; clinically relevant; concept; design; environmental carcinogenesis; mutant mouse model; prototype; tumor; tumorigenesis

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）：该提案的主要重点是研究DNA修复基因XRCC1的功能变化可以影响致癌诱导的肿瘤发生的易感性。 XRCC1已被证明是参与基础切除修复，单链断裂修复以及可能需要双链断修复的关键参与者。已经确定了许多XRCC1多态性，并且癌症协会的研究受到了广泛的流行病学关注，但结果矛盾。为了帮助验证DNA修复，特别是XRCC1的重要生物学作用，在环境致癌作用中，我们建议使用代表人类单倍不足和多态性的突变小鼠模型。 XRCC1没有已知的酶活性，但取决于蛋白质与蛋白质相互作用以在DNA修复中发挥作用。因此，使用诸如小鼠之类的生物系统来帮助定义与可观察到的肿瘤表型相关的功能，这是研究XRCC1功能的主要手段。甲氧基烷烷（AOM）是一种烷基化剂，并且是在结肠中具有肿瘤前，恶性和恶性病变的小鼠中建立的癌致癌，并且在较小程度上是肝脏的。它也是存在潜在的暴露风险的环境中存在的烷基化剂的原型。我们的假设是，癌症对AOM的敏感性可能会受到XRCC1单倍不足的不足和单核苷酸多态性R194W和R280H的影响。从我们提出的研究中产生的信息可用于帮助设计临床相关的研究，以识别可能增加特定环境状况的癌症风险的个人或群体。公共卫生相关性：该提案的主要重点是调查DNA修复基因XRCC1的功能变化可以影响致癌诱导的肿瘤发生的易感性。 XRCC1已被证明是参与基础切除修复，单链断裂修复以及可能需要双链断修复的关键参与者。已经确定了许多XRCC1多态性，并且癌症协会的研究受到了广泛的流行病学关注，但结果矛盾。为了帮助验证DNA修复，特别是XRCC1的重要生物学作用，在环境致癌作用中，我们建议使用代表人类单倍不足和多态性的突变小鼠模型。