Aging and Mutation Load in Transgenic Medaka Fish

转基因大蓝色突变检测系统的Medaka鱼（Oryzias latipes）是直接在体内分析年龄和突变负荷（突变频率和模式）的极好模型，同时考虑了相关参数，如组织类型和某些环境条件，包括温度。该系统为小鼠与非哺乳动物脊椎动物的突变方面的比较提供了一个新的模型。核心假设是，与衰老相关的突变过程在所有脊椎动物中大致相似，这意味着先前在小鼠中关于衰老的自发突变频率和模式的观察结果将在非哺乳动物脊椎动物——medaka中观察到。此外，medaka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（C. elegans和D. melanogaster）有明显不同。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接近的进化关系（即，鱼和老鼠之间的进化距离（约450万年）大于老鼠和人类之间的进化距离（约65万年）），鱼类到老鼠的自发突变的进化守恒可能可以外推到人类身上。该项目的目的是确定在三种不同温度下维持幼鱼和老鱼的体细胞组织和种系中的突变负荷。预计该研究结果将提供有关老年组织类型和温度突变负荷的初步数据。试验数据对规划未来的实验很重要。在此之前，不可能比较影响远亲脊椎动物物种自发诱变的各种参数（即年龄、组织类型和温度）。

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.