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

描述(申请人提供)：在秀丽线虫和相关线虫中，Dauer信息素是进入发育受阻的Dauer幼虫阶段的主要线索，其活性被一种未表征的‘食物信号’所拮抗。在许多方面类似于群体感应分子，达尔信息素由线虫结构性地分泌到环境中，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调节TGFP和胰岛素/IGF-1途径，这些途径调节Dauer的发育，也控制线虫和高等生物的新陈代谢和衰老。达尔信息素的几种成分已被鉴定为双脱氧糖子囊糖的衍生物，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。为了研究Dauer信息素的性质，我们将1)鉴定Dauer信息素所有活性成分的化学结构和调节其产生的环境条件，2)使用上位性分析来研究它们的作用机制，3)通过生物合成突变体的特征和通过对额外的生物合成基因进行候选RNAi筛选来研究它们的生物合成，以及4)从几个相关线虫物种中鉴定Dauer信息素的化学结构和跨物种活性。为了表征拮抗达尔信息素的食物信号，我们将利用上位性分析鉴定其化学结构并探讨其作用机制。最后，为了识别针对TGFP和胰岛素/IGF-1途径的合成小分子，我们将对抑制Dauer形成或诱导Dauer恢复的分子进行高通量筛选。这一筛选可能会识别出新型驱虫剂。总之，识别达尔信息素和食物信号并表征它们的作用机制对于我们理解来自环境的化学感觉信号如何影响线虫和高等生物体的发育、新陈代谢和衰老等基本过程至关重要。 相关性：环境信号，如信息素和基于食物的线索，控制着小蛔虫线虫的发育、新陈代谢和衰老过程。我们将研究这些信号的化学性质以及它们如何调节蛔虫的发育。这项工作将为深入了解环境因素对人类新陈代谢和衰老的影响提供依据。

DESCRIPTION (provided by applicant): 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 and 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 of the dauer pheromone, we will 1) identify the chemical structures of all active components of the 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. Relevance: Environmental signals such as pheromones and food-based cues control the development, metabolism, and aging process in the small roundworm C. elegans. We will investigate the chemical nature of these signals and how they modulate development in roundworms. This work will provide insights into the influence of environmental factors on metabolism and aging in humans.