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: 7896672
• 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 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7896672
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affect; Age; Age of Onset; Aging; Aging-Related Process; Biochemical; Bioinformatics; Biological; Biological Models; Biological Process; Boxing; Caenorhabditis elegans; Cells; Complex; Coupled; Coupling; Data; Defect; Development; Diabetes Mellitus; Diapause; Family; Family member; Fatty acid glycerol esters; Gene Targeting; Genes; Genetic Transcription; Genome Stability; Genomics; Goals; Gonadal structure; Health; IGF-1 Signaling Pathway; Individual; Insulin; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Lead; Lesion; Location; Longevity; Mammals; Metabolism; Methods; Molecular; Molecular Genetics; Nature; Nematoda; Obesity; Organism; Orthologous Gene; Output; Pathway interactions; Phenotype; Physiological Processes; Population; Process; Proteins; Protocols documentation; Regulation; Resistance; Resistance development; Role; Signal Transduction; Signaling Pathway Gene; Specificity; Stress; System; Technology; Testing; To specify; aging population; cell type; chromatin immunoprecipitation; combat; dosage; forkhead protein; genome wide association study; genome-wide; insight; mutant; neuronal cell body; programs; protein function; receptor

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.

在接下来的几年中，美国年龄较大的人数将大大增加。与这种老龄化人口相关的人将大量增加与年龄相关疾病的病例。 理解分子水平的衰老过程无疑会提供对抗这些疾病的重要线索。我们试图通过延迟与年龄相关疾病的发作来提高个人的健康。过去十年中，许多实验室的衰老研究揭示了 Forkhead转录家庭（Foxo）。在这里，我们将线虫，秀丽隐杆线虫用作我们的模型系统，因为它拥有一个保存完好的FOXO家庭成员DAF-16。这种蛋白质水平的改变会导致寿命变化，脂肪储存，乳不滞育和抗压力。我们试图定义DAF-16如何协调其多个输入和输出信号，以指定多个发展程序，例如寿命，脂肪存储，压力抗性和发展。为了实现这一目标，我们将使用尖端技术首先识别DAF-16相互作用的蛋白质并确定它们如何影响目标选择。其次，我们将使用基因组范围的方法定义DAF-16直接目标。这些研究将推向对衰老过程的生化和基因组理解。此外，我们定义一种蛋白质如何调节多个过程。在这一途径中，蠕虫和哺乳动物之间的高度保护表明，这些研究无疑也对我们对哺乳动物衰老过程的理解有影响。