TRANSGENIC MOUSE MODELS OF LONGEVITY

衰老的过程伴随着年龄的逐渐下降 大多数器官系统的功能。减少的质量和功能 骨骼肌的能力在很大程度上导致了 在动物和人类中，随着年龄的增长而产生的机车性能。 尽管与年龄相关的肌肉功能退化已经足够 有文献记载的，潜在的分子机制；选择性肌肉纤维 衰老哺乳动物的萎缩目前尚不清楚，因此具有治疗作用。 旨在保持功能和再生能力的课程 老化的肌肉一直很难设计。本研究将 直接解决哺乳动物年龄相关性萎缩的分子基础 通过研究新基因c-ski在骨骼肌中的功能 选择性地维持肌肉纤维的大小、组成和 再生能力。携带额外c-ski基因拷贝的转基因小鼠 基因显示细胞肥大正是那些肌肉纤维 在老化过程中受到的影响最大。我们最近 首次发现纤维特异性基因(肌球蛋白轻链) 骨骼肌细胞中SKI作用的已知遗传靶点促使 本申请中概述的实验课程。第一部分 该项目将利用我们对肌球蛋白轻链的广泛知识 基因调控，以及对小鼠品系的表征 携带SKI和肌球蛋白轻链转基因构建分子模型 对于SKI基因表达的肥大效应，在肌肉细胞中 培养和老化的动物。这一模式将提供基本的 为了我们的长期研究目标，设计一种基因疗法 旨在保持骨骼肌系统完整性的方法 垂暮之年。该项目的第二部分利用了我们在 基因表达分析和转基因小鼠技术，在 与几个实验室的合作努力。我们将共同评估 候选长寿保障基因对人的潜在影响 转基因动物的发育和衰老，我们自己的分析 骨骼肌肉系统。具体地说，我们将产生转基因小鼠 携带第一个克隆的长寿基因LAG1的哺乳动物同源物 酵母中的保证基因，以及与果蝇可能的哺乳动物同源物 当它们被识别时会滞后。这些老鼠的特征将提供 对滞后在发展中和在不同国家的作用的洞察 组织，并可能构成进一步研究的有价值的模型 哺乳动物长寿的遗传参数。

The process of aging is accompanied by a gradual decline in the performance of most organ systems. The decreased mass and functional capability of skeletal muscles contribute largely to the impairment of locomotive performance that accompanies aging in both animals and humans. Although age-related degeneration in muscle functions has been amply documented, the molecular mechanisms underlying; selective muscle fiber atrophy in aging mammals are currently unknown, and therefore therapeutic courses aimed at maintaining functional and regenerative capacities in aging muscles have been difficult to design. The present study will directly address the molecular basis of age-related atrophy in mammalian skeletal muscle by investigating the function of a novel gene, c-ski, in the selective maintenance of muscle fiber size, composition, and regenerative capacity. Transgenic mice carrying extra copies of the c-ski gene display cell hypertrophy of precisely those muscle fibers which are most dramatically affected during the aging process. Our recent identification of a fiber-specific gene (myosin light chain) as the first known genetic target for ski action in skeletal muscle cells has prompted the experimental course outlined in this application. The first part of the project will draw upon our extensive knowledge of myosin light chain gene regulation, as well as the characterization of mouse lines both carrying ski and myosin light chain transgenes, to build a molecular model for the hypertrophic effects of ski gene expression, both in muscle cell culture and in the aging animal. This model will provide the basic information for our long-term research goal, to design a gene therapeutic approach aimed at maintaining the integrity of the skeletal muscle system in old age. The second part of the project exploits our experience with analysis of gene expression and transgenic mouse technology, in collaborative efforts with several laboratories. Together we will assess the potential effects of candidate longevity assurance genes on the development and aging of transgenic animals, focussing our own analysis on the skeletal musculature. Specifically, we will generate transgenic mice carrying the mammalian homolog of LAG1, the first cloned longevity assurance gene in yeast, and putative mammalian homologs to Drosophila LAGs as they are identified. Characterization of these mice will provide insights into the function of LAGs during development and in different tissues, and will potentially comprise a valuable model for further study of genetic parameters of longevity in mammals.