Aging and Mutation Load in Transgenic Medaka Fish

转基因青鳉鱼的衰老和突变负荷

• 批准号: 6477868
• 负责人: STEVE Seev SOMMER
• 金额: $ 8.75万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6477868
• 关键词: age difference; aging; alternatives to animals in research; biochemical evolution; gene environment interaction; gene frequency; gene mutation; genetic models; genetically modified animals; liver; longevity; male; medaka; nucleic acid sequence; temperature; testis; tissue /cell preparation

Medaka fish (Oryzias latipes) transgenic for the Big Blue mutation detection system are an excellent model for direct in vivo analysis of age and mutation load (mutation frequency and pattern) with consideration of associated parameters such as tissue type and certain environmental conditions, including temperature. This system provides a novel model for comparison of aspects of mutagenesis in the mouse with those in a non-mammalian vertebrate. The central hypothesis is that the mutational process as it relates to aging is broadly similar among all vertebrates implying that previous observations made regarding spontaneous mutation frequency and pattern with aging in the mouse will be observed in a non-mammalian vertebrate, the medaka. In addition, medaka fish provide a new vertebrate model of aging with distinct differences from mammalian models and the popular invertebrate models of aging (C. elegans and D. melanogaster). It is expected that temperature is a major determinant of longevity in fish. The rationale for use of a fish model in aging research is that the evolutionary conservation of spontaneous mutations from fish to mouse can likely by extrapolated to humans given the closer evolutionary relationship between rodents and humans (i.e., the evolutionary distance between fish and mouse (about 450 megayears) is greater than mouse and human (about 65 megayears)). The objective for the project is to determine the mutations load in a somatic tissue and the germline in young and old fish maintained at three different temperatures. It is anticipated that the findings will provide preliminary data regarding mutation load in old age with tissue type and temperature. The pilot data will be important for planning future experiments. Prior to this proposal, it was not possible to compare the various parameters (i.e., age, tissue type and temperature) affecting spontaneous mutagenesis in distantly related vertebrate species.

Big Blue 突变检测系统转基因青鳉鱼 (Oryzias latipes) 是直接体内分析年龄和突变负荷（突变频率和模式）的绝佳模型，同时考虑到组织类型和某些环境条件（包括温度）等相关参数。该系统提供了一种用于比较小鼠与非哺乳动物脊椎动物诱变方面的新模型。中心假设是，与衰老相关的突变过程在所有脊椎动物中大致相似，这意味着先前对小鼠衰老过程中自发突变频率和模式的观察也将在非哺乳动物脊椎动物青鳉中观察到。此外，青鳉鱼提供了一种新的脊椎动物衰老模型，与哺乳动物模型和流行的无脊椎动物衰老模型（秀丽隐杆线虫和黑腹果蝇）有明显区别。预计温度是鱼类寿命的主要决定因素。在衰老研究中使用鱼类模型的基本原理是，考虑到啮齿动物和人类之间更密切的进化关系（即鱼和小鼠之间的进化距离（约450兆年）比小鼠和人类（约65兆年）还要大。该项目的目标是确定维持在三种不同温度下的幼鱼和老鱼的体细胞组织和种系中的突变负荷。预计这些发现将提供有关老年突变负荷与组织类型和温度的初步数据。试点数据对于规划未来的实验非常重要。在此提议之前，不可能比较影响远缘脊椎动物物种自发突变的各种参数（即年龄、组织类型和温度）。