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MOUSE MODEL FOR OXIDATIVE DNA DAMAGE REPAIR

用于氧化 DNA 损伤修复的小鼠模型

基本信息

批准号：
6689632
负责人：
JEFFREY H MILLER
金额：
$ 30.5万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-01-30 至 2005-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6689632
关键词：
DNA repair cell growth regulation disease /disorder model embryo /fetus tissue /cell culture fibroblasts gene mutation gene targeting genetically modified animals laboratory mouse neoplasm /cancer genetics oncoproteins oxidative stress p53 gene /protein

项目摘要

The long term goal of this research program is to uncover and understand mutational pathways, the DNA repair processes that counteract these pathways, and the consequences of repair defects. This proposal is an extension of previous work that defined new "mutator strains" in bacteria that have higher mutation rates than wild-type and that led to the elucidation of the GO system for oxidative damage. The human mutt gene, an essential component of this system, has been cloned. This work has now been extended to include targeted gene knockout mice. This proposal seeks to engineer and characterize a set of knockout mice lacking oxidative repair, as well as mice lacking different combinations of repair enzymes. Lacking certain repair systems can lead to cancer susceptibilities. It is therefore important to determine whether the absence of repair systems for oxidative damage leads to increased cancer rates or other abnormalities, such as accelerated aging. Specifically, the proposed research seeks to do the following. 1. Generate a double knockout mouse of mMYH with a DNA repair gene mOGG1. The OGG1 gene encodes a protein with a function similar to the bacterial MutM protein. Double knockouts might be expected to lack the ability to repair certain types of oxidative damage to the DNA. 2. Characterize mMYH knockout mice and mMYH-/- mOGG1-/- double knockout mice, analyze their phenotype and screen for abnormalities and cancer susceptibilities that might result from the reduced ability to repair oxidative damage. 3. Characterize primary mouse embryonic fibroblasts derived from both MYH-/- and MYH-/- OGG1-/- mice. 4. Generate and characterize additional combinations of mMYH knockout mice with other repair gene or tumor suppressor gene knockouts, such as MSH2 and p53.

该研究项目的长期目标是发现和了解突变途径、抵消这些途径的 DNA 修复过程以及修复缺陷的后果。该提案是先前工作的延伸，该工作定义了细菌中新的“突变菌株”，其突变率高于野生型，并阐明了 GO 系统的氧化损伤。该系统的重要组成部分人类mutt基因已被克隆。这项工作现已扩展到包括靶向基因敲除小鼠。该提案旨在设计和表征一组缺乏氧化修复的基因敲除小鼠，以及缺乏不同修复酶组合的小鼠。缺乏某些修复系统会导致癌症易感性。因此，确定氧化损伤修复系统的缺失是否会导致癌症发病率增加或其他异常（例如加速衰老）非常重要。具体来说，拟议的研究旨在做到以下几点。 1. 生成带有 DNA 修复基因 mOGG1 的 mMYH 双敲除小鼠。 OGG1基因编码一种与细菌MutM蛋白功能相似的蛋白质。双敲除可能缺乏修复 DNA 某些类型氧化损伤的能力。 2. 鉴定 mMYH 敲除小鼠和 mMYH-/- mOGG1-/- 双敲除小鼠的特征，分析其表型并筛选可能因氧化损伤修复能力降低而导致的异常和癌症易感性。 3. 表征源自 MYH-/- 和 MYH-/- OGG1-/- 小鼠的原代小鼠胚胎成纤维细胞。 4. 生成并表征 mMYH 敲除小鼠与其他修复基因或肿瘤抑制基因敲除（例如 MSH2 和 p53）的其他组合。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cells deficient in oxidative DNA damage repair genes Myh and Ogg1 are sensitive to oxidants with increased G2/M arrest and multinucleation.

DOI：
10.1093/carcin/bgn033
发表时间：
2008-04
期刊：
Carcinogenesis
影响因子：
4.7
作者：
Yali Xie;Hanjing Yang;Jeffrey H. Miller;D. Shih;G. Hicks;Jiuyong Xie;R. Shiu
通讯作者：
Yali Xie;Hanjing Yang;Jeffrey H. Miller;D. Shih;G. Hicks;Jiuyong Xie;R. Shiu

RANTES expression is a predictor of survival in stage I lung adenocarcinoma.

DOI：
发表时间：
2002-12
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
C. Moran;D. Arenberg;Chiang-Ching Huang;T. Giordano;Dafydd G. Thomas;David E. Misek;Guoan Chen;
通讯作者：
C. Moran;D. Arenberg;Chiang-Ching Huang;T. Giordano;Dafydd G. Thomas;David E. Misek;Guoan Chen;