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Small-molecule signals controlling nematode development

控制线虫发育的小分子信号

基本信息

批准号：
9896885
负责人：
Rebecca A Butcher
金额：
$ 23.66万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9896885
关键词：
Agriculture Anabolism Animals Area Bacteria Behavior Biological Biological Assay Caenorhabditis elegans Chemical Structure Chemicals Complex Data Development Egg Shell Environment Enzymes Fatty Acids G-Protein-Coupled Receptors Gene Expression Genes Human Hybrids Image In Vitro Indoles Insulin Insulin Signaling Pathway Length Life Cycle Stages Link Livestock Longevity Mass Spectrum Analysis Metabolic Metabolism Modeling Modification NMR Spectroscopy Nematoda Neurons Nutrient Organic Synthesis Organism Parasites Parasitic nematode Pathway interactions Peptides Pheromone Phosphotransferases Physiology Play Population Population Density Production Pyruvate Dehydrogenase Complex RNA interference screen Recovery Regulation Research Resistance Role Side Signal Pathway Signal Transduction Signaling Molecule Stable Isotope Labeling Starvation Stress Structure Testing Work carbonyl group comparative enzyme activity experimental study fungus in vitro activity insulin signaling interdisciplinary approach interest knock-down metabolome metabolomics mutant novel overexpression peptide synthase polyketide synthase programs public health relevance small molecule stereochemistry sugar tool

项目摘要

The proposed research program will develop a comprehensive understanding of the chemical structures, biosynthesis, and mechanism of the secondary metabolites used by the nematode Caenorhabditis elegans to control its development and physiology. We will focus on two important types of chemical signals: (1) The dauer pheromone, which C. elegans uses to induce development of the stress-resistant, dauer larval stage at high population densities. (2) A complex hybrid polyketide/ nonribosomal peptide (PK/NRP), which we have recently identified and shown is important for starvation-induced larval arrest. The dauer pheromone consists of several derivatives of the 3,6-dideoxy-L-sugar ascarylose, with different fatty acid-derived side chains. These ascarosides target G protein-coupled receptors in chemosensory neurons and downregulate the insulin and TGF pathways, which regulate dauer formation, metabolism, and lifespan in C. elegans. In Aim 1 of this proposal, we will use a multi-disciplinary approach, including metabolomics, in vitro enzyme assays, organic synthesis of biosynthetic intermediates, and RNAi-based screens, to provide a general framework for ascaroside biosynthesis and its regulation. Our preliminary results, which show that secondary metabolism in C. elegans is closely tied to primary metabolism, have uncovered new, surprising roles for primary metabolic enzymes in ascaroside biosynthesis. We will investigate how different environmental conditions alter specific signaling pathways and downstream ascaroside biosynthetic enzymes, in order to modulate the chemical message that C. elegans communicates to the population. Thus, our work will establish when and how and why C. elegans produces different pheromones. At the fundamental level, these results will enable connections to be made regarding how animals respond to a changing environment and modulate their development and physiology, accordingly. In Aim 2 of this proposal, we will identify a complex hybrid PK/NRP produced by C. elegans. Although it has been noted that a few animals, including C. elegans, contain polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) genes, very little is known about these genes. Thus, we are breaking new ground in our work to characterize the structure, biosynthesis, and biological role of the PK/NRP. The domains in the C. elegans PKS/NRPS diverge significantly from those found in bacteria and fungi, and thus, by characterizing these domains, we will uncover unique enzymes and biosynthetic strategies. Our data suggest that the hybrid PK/NRP acts upstream of the insulin pathway and facilitates the metabolic changes that need to occur during starvation-induced larval arrest. The ascarosides and the PK/NRP are conserved chemical signals that are critical for the development and survival of many nematode species, including parasitic ones. Thus, our work will enable the development of chemical tools to interfere with the life cycles of parasitic nematodes and reduce their survival.

拟议的研究计划将发展对化学结构的全面了解，生物合成，和机制的次级代谢产物的线虫，控制其发育和生理。我们将重点讨论两种重要的化学信号：（1） dauer信息素，C. elegans用于诱导发育的抗应激，dauer幼虫阶段，人口密度高。(2)一个复杂的杂合聚酮/非核糖体肽（PK/NRP），我们有最近发现和显示是重要的饥饿诱导的幼虫逮捕。道尔信息素由具有不同脂肪酸衍生侧链的3，6-双脱氧-L-糖Ascarylose的几种衍生物。这些子囊苷靶向化学感受神经元中的G蛋白偶联受体，并下调胰岛素和TGF β通路，它们调节着C.优美的目标1 建议，我们将使用多学科的方法，包括代谢组学，体外酶测定，有机生物合成中间体的合成和基于RNAi的筛选，以提供一个通用框架， Ascaroside的生物合成及其调控我们的初步结果表明， C.线虫与初级代谢密切相关，发现了初级代谢的新的，令人惊讶的作用，酶在蛔虫苷生物合成中的作用。我们将研究不同的环境条件如何改变特定的信号通路和下游Ascaroside生物合成酶，以调节该化学物质消息说，C。elegans与人群交流。因此，我们的工作将确定何时以及如何，为什么C。线虫产生不同的信息素。在基础层面，这些结果将使关于动物如何应对不断变化的环境并调节其发育和生理学。在本提案的目标2中，我们将确定一种复杂的混合PK/NRP 由C.优雅的虽然已经注意到一些动物，包括C。优雅，包含聚酮合成酶（PKS）和非核糖体肽合成酶（NRPS）基因，很少有人知道这些基因。因此，我们在我们的工作中开辟了新的天地，以表征结构，生物合成， PK/NRP的生物学作用。C. elegans PKS/NRPS显著偏离在细菌和真菌中发现，因此，通过表征这些结构域，我们将发现独特的酶，生物合成策略我们的数据表明，混合PK/NRP作用于胰岛素途径的上游，促进了饥饿诱导的幼虫停滞期间需要发生的代谢变化。Ascarosides PK/NRP是保守的化学信号，对许多人的发育和生存至关重要。线虫物种，包括寄生虫。因此，我们的工作将使化学工具的发展，干扰寄生线虫的生命周期并降低其存活率。