Natural and Synthetic Small-Molecule Modulators of Dauer Development in Nematodes

线虫 Dauer 发育的天然和合成小分子调节剂

• 批准号: 8035471
• 负责人: Rebecca A Butcher
• 金额: $ 24.65万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-09 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8035471
• 关键词: Adult; Aging; Aging-Related Process; Anabolism; Anthelmintics; Biological Assay; Biological Factors; Caenorhabditis elegans; Chemical Structure; Chemicals; Collaborations; Cues; Development; Ecology; Environment; Environmental Risk Factor; Equipment; Escherichia coli; Evolution; Fatty acid glycerol esters; Fee-for-Service Plans; Fluorescent Dyes; Food; Fractionation; Funding Opportunities; Genes; Genetic Epistasis; Goals; Grant; High Pressure Liquid Chromatography; Human; In Vitro; Insulin; Insulin-Like Growth Factor I; Laboratories; Libraries; Life; Longevity; Metabolism; Methods; Molecular Structure; Monitor; Nature; Nematoda; Organism; Pathway interactions; Phase; Phenotype; Pheromone; Population Density; Process; Production; Progress Reports; RNA Interference; Recovery; Reporter; Resistance; Sampling; Screening procedure; Signal Pathway; Signal Transduction; Staging; Stress; Structure; Temperature; Testing; Universities; Work; base; enzyme activity; high throughput screening; insight; interest; medical schools; mutant; novel; prevent; quorum sensing; receptor; research study; small molecule; sugar; tyvelose; uptake

In Caenorhabditis elegans and related nematodes, the dauer pheromone is the primary cue for entry into the developmentally arrested, dauer larval stage, and Its activity is antagonized by an uncharacterized 'food signal'. Similar in many respects to a quorum-sensing molecule, the dauer pheromone is constitutively secreted into the environment by the nematode, and thus enables the nematode to sense its population density. Dauer pheromone and food signal are thought to modulate the TGFp and insulin/IGF-1 pathways, which regulate dauer development and also control metabolism and aging in C. elegans arid in higher organisms. Several components of the dauer pheromone have been Identified as derivatives of the dideoxy sugar ascarylose, but additional unidentified components of the dauer pheromone contribute to its activity. Furthermore, the components that are produced vary depending on environmental conditions. In order to investigate the nature ofthe dauer pheromone, we will 1) identify the chemical structures of all active components ofthe dauer pheromone and the environmental conditions that modulate their production, 2) investigate their mechanism of action using epistasis analysis, 3) investigate their biosynthesis by characterization of biosynthetic mutants and by performing a candidate RNAi screen for additional biosynthetic genes, and 4) identify the chemical structures and cross-species activities of the dauer pheromone from several related nematode species. In order to characterize the food signal that antagonizes the dauer pheromone, we will identify Its chemical structure and investigate its mechanism of action using epistasis analysis. Lastly, in order to identify synthetic small molecules that target the TGFp and insulin/IGF- 1 pathways, we will perform a high-throughput screen for molecules that either suppress dauer formation or induce dauer recovery. This screen could potentially identify novel anthelmintics. In summary, identifying the dauer pheromone and the food signal and characterizing their mechanism of action are critical to our understanding of how chemosensory cues from the environment can influence such fundamental processes as development, metabolism, and aging in nematodes and in higher organisms.

在秀丽隐杆线虫和相关线虫中，dauer信息素是进入线虫的主要线索。 发育停滞，幼仔阶段，其活动被一种未表征的食物所拮抗 信号。在许多方面类似于群体感应分子，dauer信息素是组成型的。 由线虫分泌到环境中，从而使线虫能够感知其种群 密度的Dauer信息素和食物信号被认为调节TGF β和胰岛素/IGF-1途径， 调控幼仔发育，也控制C.在较高的干旱 有机体Dauer信息素的几种成分已被鉴定为双脱氧的衍生物。 糖，但额外的身份不明成分的dauer信息素有助于其活动。 此外，所生产的组件根据环境条件而变化。为了 研究道尔信息素的性质，我们将1）确定所有活性物质的化学结构 dauer信息素的成分和调节其产生的环境条件，2） 用上位性分析研究它们作用机制，3）用 生物合成突变体的表征，并通过进行候选RNAi筛选， 生物合成基因，4）鉴定道尔的化学结构和跨物种活性 几种相关线虫的信息素。为了表征食物信号， dauer信息素，我们将确定其化学结构，并研究其作用机制，使用 上位性分析最后，为了鉴定靶向TGF β和胰岛素/IGF-1的合成小分子， 1途径，我们将进行高通量筛选的分子，无论是抑制dauer形成， 诱导Dauer恢复。这种筛选可能会发现新的驱虫剂。总之，识别 dauer信息素和食物信号，并描述其作用机制，是我们的关键， 了解来自环境的化学感受线索如何影响这些基本过程 如线虫和高等生物的发育、代谢和衰老。