Identification of Genetic Modifiers of Sarcopenia in C. elegans

描述（由申请人提供）：所附申请描述了一个为期两年的探索性研究项目，旨在开始识别非寄生线虫秀丽隐杆线虫肌肉减少症的遗传修饰因子。肌肉减少症是指在人们衰老过程中不同程度发生的肌肉质量和肌肉力量的损失。由此导致的肌肉力量丧失会导致老年人身体功能受损，并成为丧失独立性、需要养老院安置、最终死亡的风险因素。对脊椎动物和人类的研究已经为多种机制提供了证据，但针对其中一些机制的临床研究只能产生适度的结果。例如，临床研究使用外源性睾酮或生长激素来补充一些老年人体内低水平的睾酮或生长激素，结果只产生了轻微的肌肉力量增加。因此，迫切需要确定研究肌肉减少症的新方法，并确定可能更易于干预的机制。我们建议使用线虫秀丽隐杆线虫来鉴定肌肉减少症的遗传修饰因子。在衰老过程中，秀丽隐杆线虫已被证明会发生肌肉减少症，这些损失似乎会导致活动能力下降，并成为死亡的一个危险因素。胰岛素/IGF-1受体daf-2的突变已被证明既能延长蠕虫的寿命，又能延缓肌肉减少症的发展。daf-2突变对肌肉减少症的影响可能是由于肌肉中基因表达的变化，从而增加了肌肉对衰老影响的抵抗力，延缓了肌肉减少症的发展。我们的目标是确定肌肉中daf-2信号的靶基因，并使用功能分析测试这些基因对肌肉减少症发展的影响。我们希望能找到防止肌肉减少症的基因，然后在哺乳动物和人类身上测试类似的效果。其中一些基因可能导致药物干预的目标，以预防或逆转人的肌肉减少症。

DESCRIPTION (provided by applicant): The attached application describes a two year exploratory research project designed to begin to identify genetic modifiers of sarcopenia in the non-parasitic nematode Caenorhabditis elegans. Sarcopenia is the loss of muscle mass and muscle strength that occurs to varying degrees during aging in people. The resulting loss of muscle strength contributes to impairments in physical functioning in older people and serves as a risk factor for loss of independence, need for nursing home placement, and ultimately mortality. Studies in vertebrate animals and humans have provided evidence for multiple mechanisms, but clinical studies using treatments aimed at addressing some of these mechanisms have produced at best modest results. For example, clinical studies that use exogenous testosterone or growth hormone to supplement low levels found in some older people have yielded only minor increases in muscle strength. Hence there is a pressing need to identify new ways to study sarcopenia and to identify mechanisms that may be more amenable to intervention. We propose to use the nematode C. elegans to identify genetic modifiers of sarcopenia. During aging, C. elegans has been shown to develop sarcopenia and these losses appear to lead to declines in mobility and serve as a risk factor for mortality. Mutations in the insulin/IGF-1 receptor daf-2 have been shown to both increase worm longevity and to delay the development of sarcopenia. These effects of daf-2 mutations on sarcopenia are likely due to changes in gene expression in the muscles that then increase the resistance of muscle to the effects of aging and delay the development of sarcopenia. We aim to identify genes that are targets of daf-2 signaling in muscle and test the effects of these genes on the development of sarcopenia using functional assays. We hope to identify genes that act to protect against sarcopenia which could then be tested for similar effects in mammals and ultimately people. Some of these genes may lead to targets for pharmacologic intervention to prevent or reverse sarcopenia in people.