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

在秀丽线虫和相关线虫中，达尔信息素是进入线虫的主要线索 发育受阻的达尔幼虫阶段，它的活动被一种没有特征的食物所对抗 信号‘。在许多方面与群体感应分子相似，达尔信息素是结构性的。 通过线虫分泌到环境中，从而使线虫能够感觉到它的种群 密度。Dauer信息素和食物信号被认为调节TGFp和胰岛素/IGF-1途径， 它们调节线虫的达尔发育，并控制线虫的代谢和衰老。 有机体。达尔信息素的几种成分已被鉴定为双脱氧的衍生物 糖子囊糖，但达尔信息素的其他未知成分有助于其活性。 此外，根据环境条件的不同，产生的成分也不同。为了 调查达尔信息素的性质，我们将1)鉴定所有活性物质的化学结构 达尔信息素的组成和调节其产生的环境条件，2) 用上位性分析研究它们的作用机制，3)研究它们的生物合成 生物合成突变体的鉴定和通过对附加的候选RNAi筛选 生物合成基因，以及4)鉴定达尔的化学结构和跨物种活性 几种近缘线虫物种的信息素。为了刻画食物信号的特性 达尔信息素，我们将鉴定其化学结构，并研究其作用机制 上位性分析。最后，为了识别针对TGFp和胰岛素/IGF的合成小分子- 1途径，我们将对抑制Dauer形成或 诱导达尔康复。这一筛选可能会识别出新型驱虫剂。总而言之，确定 Dauer信息素和食物信号及其作用机制的描述对我们的 了解来自环境的化学感觉信号如何影响这些基本过程 随着线虫和高等生物的发育、新陈代谢和衰老。

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.