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: 7642972
• 负责人: Rebecca A Butcher
• 金额: $ 9万
• 依托单位: HARVARD MEDICAL SCHOOL
• 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 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7642972
• 关键词: Adult; Aging; Aging-Related Process; Anabolism; Anthelmintics; Biological Assay; Biological Factors; Caenorhabditis elegans; Chemical Structure; Chemicals; Cues; Development; Ecology; Environment; Environmental Risk Factor; Evolution; Fatty acid glycerol esters; Food; Fractionation; Genes; Genetic Epistasis; Human; Insulin; Life; Longevity; Metabolism; Molecular Structure; Nature; Nematoda; Organism; Pathway interactions; Phenotype; Pheromone; Population Density; Principal Investigator; Process; Production; RNA Interference; Recovery; Resistance; Signal Pathway; Signal Transduction; Staging; Stress; Structure; Temperature; Testing; Work; base; high throughput screening; insight; mutant; novel; quorum sensing; research study; small molecule; sugar; tyvelose

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.

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、dauer 幼虫阶段的主要线索，其活性受到未表征的“食物信号”的拮抗。在许多方面与群体感应分子类似，多尔信息素由线虫组成型分泌到环境中，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，从而调节秀丽隐杆线虫和高等生物中的 Dauer 发育并控制新陈代谢和衰老。多尔信息素的几种成分已被鉴定为双脱氧糖蛔糖的衍生物，但多尔信息素的其他未鉴定成分也有助于其活性。此外，生产的组件根据环境条件而变化。为了研究 d​​auer 信息素的性质，我们将 1) 确定 dauer 信息素所有活性成分的化学结构以及调节其产生的环境条件，2) 使用上位分析研究其作用机制，3) 调查通过生物合成突变体的表征和对其他生物合成基因进行候选 RNAi 筛选来确定它们的生物合成，4) 鉴定其化学结构和跨物种活性来自几种相关线虫物种的多尔信息素。为了表征拮抗多尔信息素的食物信号，我们将鉴定其化学结构并使用上位分析研究其作用机制。最后，为了识别靶向 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。该屏幕可能会识别新型驱虫药。总之，识别多尔信息素和食物信号并描述其作用机制对于我们理解环境中的化学感应信号如何影响线虫和高等生物体的发育、代谢和衰老等基本过程至关重要。 相关性：信息素和食物信号等环境信号控制着小蛔虫的发育、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。这项工作将深入了解环境因素对人类新陈代谢和衰老的影响。

项目成果

Acyl-CoA oxidase complexes control the chemical message produced by Caenorhabditis elegans.

酰基辅酶A氧化酶复合物控制着秀丽隐杆线虫产生的化学信息。

• 发表时间: 2015-03-31
• 影响因子: 11.1
• 作者: Zhang, Xinxing;Feng, Likui;Chinta, Satya;Singh, Prashant;Wang, Yuting;Nunnery, Joshawna K;Butcher, Rebecca A
• 通讯作者: Butcher, Rebecca A

Feeding state regulates pheromone-mediated avoidance behavior via the insulin signaling pathway in Caenorhabditis elegans.

进食状态通过秀丽隐杆线虫的胰岛素信号通路调节信息素介导的回避行为。

• 发表时间: 2018-08-01
• 作者: Ryu, Leesun;Cheon, YongJin;Huh, Yang Hoon;Pyo, Seondong;Chinta, Satya;Choi, Hongsoo;Butcher, Rebecca A;Kim, Kyuhyung
• 通讯作者: Kim, Kyuhyung

A sexually conditioned switch of chemosensory behavior in C. elegans.

线虫化学感应行为的性条件转换。

• 发表时间: 2013
• 影响因子: 3.7
• 作者: Sakai, Naoko;Iwata, Ryo;Yokoi, Saori;Butcher, Rebecca A;Clardy, Jon;Tomioka, Masahiro;Iino, Yuichi
• 通讯作者: Iino, Yuichi

An indole-containing dauer pheromone component with unusual dauer inhibitory activity at higher concentrations.

一种含有吲哚的多尔信息素成分，在较高浓度下具有不寻常的多尔抑制活性。

• DOI: 10.1021/ol901011c
• 发表时间: 2009-07-16
• 期刊: Organic letters
• 影响因子: 5.2
• 作者: Butcher RA;Ragains JR;Clardy J
• 通讯作者: Clardy J

Olfactory plasticity is regulated by pheromonal signaling in Caenorhabditis elegans.

秀丽隐杆线虫的嗅觉可塑性受信息素信号调节。

• 发表时间: 2010-09-24
• 作者: Yamada, Koji;Hirotsu, Takaaki;Matsuki, Masahiro;Butcher, Rebecca A;Tomioka, Masahiro;Ishihara, Takeshi;Clardy, Jon;Kunitomo, Hirofumi;Iino, Yuichi
• 通讯作者: Iino, Yuichi