Dissecting complex regulation by C. elegans DAF-16

解析秀丽隐杆线虫 DAF-16 的复杂调控

• 批准号: 7655731
• 负责人: HEIDI A TISSENBAUM
• 金额: $ 41万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7655731
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affect; Age; Age of Onset; Aging; Aging-Related Process; Biochemical; Biological; Biological Models; Biological Process; Caenorhabditis elegans; Colorado; Complex; Coupled; Coupling; Data; Development; Diabetes Mellitus; Diapause; Family; Family member; Fatty acid glycerol esters; Fellowship; Gene Targeting; Genes; Genetic Transcription; Genomics; Goals; Growth; Health; Human Resources; Individual; Insulin; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Laboratories; Lead; Location; Longevity; Mammals; Metabolism; Methods; Molecular; Molecular Genetics; Nematoda; Obesity; Organism; Orthologous Gene; Output; Pathway interactions; Phosphorylation; Population; Postdoctoral Fellow; Process; Proteins; Protocols documentation; Regulation; Resistance; Resistance development; Role; Signal Pathway; Signal Transduction; Specificity; Stress; System; Technology; Testing; To specify; Work; aging population; chromatin immunoprecipitation; combat; dosage; forkhead protein; genome wide association study; genome-wide; insight; programs; protein function; receptor; research study

Over the next several years, the number of older individuals in the U.S. population will increase dramatically. Associated with this aging population, will be a large surge in the number of cases of age-associated illnesses. Understanding the aging process at the molecular level will undoubtedly give important clues to combat these illnesses. We seek to increase the health of individuals by delaying the onset of age-associated illnesses. Studies on aging over the past decade from many labs have revealed the importance of the forkhead transcription family (FOXO). Here, we use the nematode, C. elegans as our model system because it has a single well-conserved FOXO family member, DAF-16. Altering levels of this protein lead to changes in life span, fat storage, dauer diapause and stress resistance. We seek to define how daf-16 coordinates its multiple input and output signals to specify multiple developmental programs such as life span, fat storage, stress resistance, and development. To accomplish this goal, we will use cutting edge technologies to first identify DAF-16 interacting proteins and determine how they influence target choice. Second, we will define DAF-16 direct targets using genome wide approaches. These studies will which push towards a biochemical and genomic understanding of the aging process. In addition, we define how one protein can regulate multiple processes. The high degree of conservation between worms and mammals in this pathway indicate that these studies will also undoubtedly have implications for our understanding of the mammalian aging process.

未来几年，美国人口中老年人的数量将急剧增加。与人口老龄化相关的是，与年龄相关的疾病的病例数量将大幅增加。 从分子水平了解衰老过程无疑将为对抗这些疾病提供重要线索。我们寻求通过延迟与年龄相关的疾病的发作来增强个人的健康。许多实验室过去十年对衰老的研究揭示了衰老的重要性 叉头转录家族（FOXO）。在这里，我们使用线虫 C. elegans 作为我们的模型系统，因为它有一个保存良好的 FOXO 家族成员 DAF-16。改变这种蛋白质的水平会导致寿命、脂肪储存、滞育和抗压能力的变化。我们试图定义 daf-16 如何协调其多个输入和输出信号，以指定多个发育程序，如寿命、脂肪储存、压力抵抗和发育。为了实现这一目标，我们将使用尖端技术首先识别 DAF-16 相互作用蛋白并确定它们如何影响靶点选择。其次，我们将使用全基因组方法定义 DAF-16 直接靶点。这些研究将推动对衰老过程的生化和基因组理解。此外，我们定义了一种蛋白质如何调节多个过程。线虫和哺乳动物之间在这一途径中的高度保守性表明，这些研究无疑也将对我们理解哺乳动物的衰老过程产生影响。