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: 8212387
• 负责人: Rebecca A Butcher
• 金额: $ 24.61万
• 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 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212387
• 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，dauer 幼虫阶段，其活动受到未表征的“食物”的拮抗 信号'。多尔信息素在许多方面与群体感应分子相似， 由线虫分泌到环境中，从而使线虫能够感知其种群 密度。 Dauer 信息素和食物信号被认为可以调节 TGFp 和胰岛素/IGF-1 途径， 调节秀丽隐杆线虫和高等动物中的多尔发育并控制新陈代谢和衰老 有机体。多尔信息素的几种成分已被鉴定为双脱氧的衍生物 糖蛔糖，但多尔信息素的其他未识别成分有助于其活性。 此外，生产的组件根据环境条件而变化。为了 研究多尔信息素的性质，我们将 1) 识别所有活性物质的化学结构 多尔信息素的成分以及调节其产生的环境条件，2) 使用上位分析研究它们的作用机制，3) 通过以下方法研究它们的生物合成 生物合成突变体的表征，并通过进行候选 RNAi 筛选来获得额外的 生物合成基因，4) 鉴定 dauer 的化学结构和跨物种活性 来自几种相关线虫物种的信息素。为了表征拮抗的食物信号 dauer 信息素，我们将鉴定其化学结构并研究其作用机制 上位分析。最后，为了鉴定靶向 TGFβ 和胰岛素/IGF-的合成小分子 1 途径，我们将对抑制 dauer 形成或 诱导 dauer 恢复。该屏幕可能会识别出新型驱虫药。总而言之，识别 多尔信息素和食物信号以及表征它们的作用机制对于我们至关重要 了解环境中的化学感应信号如何影响这些基本过程 线虫和高等生物的发育、代谢和衰老。

项目成果

Parallel evolution of domesticated Caenorhabditis species targets pheromone receptor genes.

• DOI: 10.1038/nature10378
• 发表时间: 2011-08-17
• 期刊: NATURE
• 影响因子: 64.8
• 作者: McGrath, Patrick T.;Xu, Yifan;Ailion, Michael;Garrison, Jennifer L.;Butcher, Rebecca A.;Bargmann, Cornelia I.
• 通讯作者: Bargmann, Cornelia I.