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

描述（由申请人提供）：在秀丽隐杆线虫和相关线虫中，dauer信息素是进入发育停滞的dauer幼虫阶段的主要线索，其活性被未表征的“食物信号”拮抗。在许多方面类似于群体感应分子，dauer信息素由线虫组成性分泌到环境中，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TGF β和胰岛素/IGF-1通路，从而调节Dauer的发育，并且还控制C. elegans线虫and in higher高等organisms生物.几种成分的dauer信息素已被确定为衍生物的双脱氧糖ascarylose，但额外的身份不明的成分的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）鉴定道尔信息素的所有活性组分的化学结构和调节它们产生的环境条件，2）使用上位性分析研究它们的作用机制，3）通过表征生物合成突变体和通过对另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，鉴定了几种近缘线虫的dauer信息素的化学结构和跨种活性。为了表征食物信号，拮抗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途径的合成小分子，我们将进行高通量筛选，以寻找抑制dauer形成或诱导dauer恢复的分子。这种筛选可能会发现新的驱虫剂。总之，确定dauer信息素和食物信号，并表征其作用机制是至关重要的，我们的理解如何从环境中的化学感觉线索可以影响线虫和高等生物的发育，代谢和衰老等基本过程。 相关性：信息素和食物等环境信号控制着小蛔虫的发育、代谢和衰老过程。优雅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。这项工作将为环境因素对人类新陈代谢和衰老的影响提供见解。

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.