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Identification of Biomarkers in Zebrafish Aging

斑马鱼衰老生物标志物的鉴定

基本信息

批准号：
6897474
负责人：
SHUJI KISHI
金额：
$ 8.55万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-06-01 至 2006-05-31
项目状态：
已结题

项目摘要

The zebrafish (Danio rerio) has proved to be an outstanding animal model system for genetic studies to explore vertebrate diseases as well as development. However, most zebrafish researchers evaluate their mutant animals at the embryonic and larval stages. Thus, mutations which mediate the effects of late-age onset diseases or dysfunctions have not been identified. More primitive model organisms such as Caenorhabditis elegans and Drosophila melanogaster have already been utilized quite successfully for genetic studies of aging, which have identified key evolutionarily conserved genes associated with the aging process. However, these invertebrate models cannot sufficiently identify critical longevity genes that are unique to vertebrates. Therefore it seems obvious that if the zebrafish system, with its the well-established advantages of forward genetics and recently improved reverse genetic technology, could be adapted to study aging, it would present an unparalleled opportunity to advance aging research. A number of theories to explain aging in mammals have been advanced over the years. Theories currently in vogue suggest that aging is the regulated by oxidative or genotoxic stress, telomere metabolism, regulation of caloric restriction and control of metabolic energy rate. Notably these theories are not mutually exclusive. However, compared to mammals, the aging process of zebrafish has gone almost unstudied. We propose to lay a strong foundation for aging studies in the zebrafish. First and foremost, we will perform an intensive search for biological and biochemical aging markers in zebrafish over the course of its entire lifespan (Aim 1). We will then begin to examine the effects treatments thought to regulate aging such as genotoxic stress by ionizing radiation or oxidative stress by hydrogen peroxide on the aging process of zebrafish using the most robust of our markers (Aim 2). These studies should prepare the way for later forward and reverse genetic studies where we will seek premature aging phenotypes or phenotypes resistant to aging and senescence in zebrafish.

斑马鱼（Danio rerio）已被证明是探索脊椎动物疾病和发育的遗传学研究的杰出动物模型系统。然而，大多数斑马鱼研究人员在胚胎和幼虫阶段评估其突变动物。因此，尚未鉴定出介导晚发疾病或功能障碍影响的突变。更原始的模式生物，如秀丽隐杆线虫和果蝇，已被相当成功地用于衰老的遗传学研究，这些研究已经确定了与衰老过程相关的关键的进化保守基因。然而，这些无脊椎动物模型无法充分识别关键的长寿基因脊椎动物特有的。因此，显而易见的是，如果斑马鱼系统凭借其已确立的正向遗传学优势和最近改进的反向遗传技术能够适用于研究衰老，那么它将为推进衰老研究提供无与伦比的机会。多年来，已经提出了许多解释哺乳动物衰老的理论。理论目前流行的观点认为，衰老是由氧化或基因毒性应激、端粒代谢、热量限制的调节和代谢能量速率的控制来调节的。值得注意的是，这些理论并不相互排斥。然而，与哺乳动物相比，斑马鱼的衰老过程几乎没有被研究过。我们建议为斑马鱼的衰老研究奠定坚实的基础。首先，我们将在斑马鱼的整个生命周期中深入研究生物和生化衰老标记（目标 1）。然后，我们将开始使用我们最强大的标记来检查被认为调节衰老的治疗方法的效果，例如电离辐射的基因毒性应激或过氧化氢的氧化应激对斑马鱼衰老过程的影响（目标 2）。这些研究应该为以后做好准备正向和反向遗传学研究，我们将寻找斑马鱼的过早衰老表型或抗衰老和衰老的表型。