Dissecting complex regulation by C. elegans DAF-16

在接下来的几年里，美国人口中的老年人数量将急剧增加。与人口老龄化相关的是，与年龄相关的疾病病例数量将大幅增加。 在分子水平上了解衰老过程无疑将为抗击这些疾病提供重要线索。我们寻求通过推迟与年龄相关的疾病的发生来增加个人的健康。许多实验室在过去十年中进行的关于衰老的研究揭示了 叉头转录家族(FOXO)。在这里，我们使用线虫，线虫作为我们的模型系统，因为它有一个保守的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、滞育和抗逆性的变化。我们试图定义daf-16如何协调其多个输入和输出信号，以指定多个发育计划，如寿命、脂肪储存、抗逆性和发育。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标选择。其次，我们将使用全基因组方法定义DAF-16的直接靶点。这些研究将推动对衰老过程的生化和基因组理解。此外，我们还定义了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具有重要意义。

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.