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Identification of Genetic Modifiers of Sarcopenia in C. elegans

秀丽隐杆线虫肌少症遗传修饰的鉴定

基本信息

批准号：
7384882
负责人：
ALFRED L FISHER
金额：
$ 14.54万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7384882
关键词：
Accounting Address Affect Agar Age Aging Aging-Related Process Animal Genetics Animal Model Animals Antioxidants Binding Bioinformatics Biolistics Biological Assay Biological Models Biological Preservation Caenorhabditis elegans Cellular Stress Chemicals Chemotaxis Clinical Research Cloning Computer software Cytochrome P450 Data Decompression Sickness Development Eels Elderly Engineering Enzymes Facility Construction Funding Category Financial compensation Frequencies G-Protein-Coupled Receptors Gelatin Gene Expression Gene Expression Profiling Gene Targeting Genes Genetic Genetic Crosses Genetic Recombination Genetic Screening Germ Lines Goals Gonadal Steroid Hormones Health Homologous Gene Human Image Impairment Individual Insulin Insulin-Like-Growth Factor I Receptor Intake Intervention Lateral Lead Life Link Locomotion Longevity Lower Extremity Mammals Measurable Measures Mediating Metabolic Microarray Analysis Microscope Minor Modeling Motor Motor Neurons Movement Mus Muscle Muscle Cells Muscle Contraction Muscle function Mutation Nematoda Numbers Nursing Homes Outcome Parasitic nematode Pathway interactions Pattern Performance Personal Satisfaction Physical Function Placement Poly A Poly(A)-Binding Proteins Population Process Protein-Energy Malnutrition Proteins RNA Interference Receptor Signaling Regulation Relaxation Reproduction Research Project Grants Resistance Risk Factors Screening procedure Series Signal Pathway Signal Transduction Snakes Somatotropin Speed Standards of Weights and Measures Structure Surface Testing Testosterone Time Tissues Transcript Transgenes Transgenic Animals Translating Vertebrates Viscosity age effect base day design experience falls functional decline genetic selection growth hormone deficiency human study insight instrumental activity of daily living mortality muscle strength mutant normal aging novel therapeutics prevent promoter research study response sarcopenia satellite cell size software development superoxide dismutase 1 vector

项目摘要

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.

描述（由申请人提供）：所附申请描述了一项为期两年的探索性研究项目，旨在开始鉴定非寄生线虫秀丽隐杆线虫中肌肉减少症的遗传修饰剂。肌肉减少症是人在衰老过程中不同程度发生的肌肉质量和肌肉力量的丧失。由此导致的肌肉力量丧失会导致老年人身体机能受损，并成为丧失独立性、需要入住疗养院以及最终死亡的危险因素。对脊椎动物和人类的研究为多种机制提供了证据，但旨在解决其中一些机制的临床研究最多只产生了有限的结果。例如，使用外源性睾酮或生长激素来补充某些老年人体内水平较低的临床研究仅取得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适合干预的机制。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剂。在衰老过程中，线虫已被证明会出现肌肉减少症，这些损失似乎会导致活动能力下降，并成为死亡的危险因素。胰岛素/IGF-1 受体 daf-2 的突变已被证明可以延长线虫的寿命并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并延缓肌肉减少症的发展。我们的目标是识别肌肉中 daf-2 信号传导靶标的基因，并使用功能测定测试这些基因对肌肉减少症发展的影响。我们希望找到能够预防肌肉减少症的基因，然后可以在哺乳动物和最终人类中测试这些基因是否具有类似的效果。其中一些基因可能会导致药物干预的目标，以预防或逆转人类肌肉减少症。