Ascaroside signaling and aging in Caenorhabditis elegans

秀丽隐杆线虫蛔苷信号传导与衰老

• 批准号: 7769502
• 负责人: Frank Clemens Schroeder
• 金额: $ 14.14万
• 依托单位: BOYCE THOMPSON INST FOR PLANT RESEARCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-15 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7769502
• 关键词: Adult; Affect; Age; Aging; Applications Grants; Behavior; Biological; Biological Assay; Caenorhabditis elegans; Chemicals; Complement; Development; Diabetes Mellitus; Disease; Exposure to; Gene Expression; Genes; Genetic; Genomics; Glycosides; Goals; Heart Diseases; Heat Stress Disorders; Human; Incentives; Incidence; Investigation; Knowledge; Life; Link; Longevity; Malignant Neoplasms; Measures; Mediating; Metabolic; Modeling; Molecular; Molecular Probes; Nematoda; Nuclear Hormone Receptors; Organism; Osteoporosis; Partner in relationship; Pathway interactions; Phenotype; Pheromone; Physiological; Research; Resistance; Role; Sampling; Sex Attractants; Signal Transduction; Signaling Molecule; Staging; Testing; age effect; age related; feeding; follow-up; in vivo; interest; knock-down; mutant; nervous system disorder; novel strategies; programs; public health relevance; research study; sex; small molecule; synergism; tool; transcription factor

DESCRIPTION (provided by applicant): In the nematode Caenorhabditis elegans, several groups of small molecules control genetic pathways as intrinsic molecular messengers. A group of glycosides, the ascarosides, have recently been shown to induce development arrest (dauer formation) and, furthermore to act as sex pheromones. Our preliminary results show that ascarosides not only act as dauer or mating signals, but also strongly influence adult lifespan and thermotolerance. Therefore, ascaroside signaling provides a direct link between developmental arrest and aging, and offers a unique set of tools to identify and probe the corresponding molecular pathways. The principal goal of this proposal is to determine the genetic pathways involved in ascaroside-mediated increases in Lifespan and thermotolerance. For this purpose synthetic samples of the endogenously produced ascarosides will be employed in a novel approach that combines chemical genomics with recently acquired knowledge about the biological roles of these signaling molecules. Using synthetic samples of the eight so-far identified ascarosides, the effect of various concentrations and combinations of these compounds on thermotolerance and lifespan in the wildtype worms will be determined. Subsequently, ascarosides or ascaroside-combinations with strong thermotolerance or lifespan phenotypes will be assayed in additional thermotolerance assays against a selection of mutants of key genetic pathways known to be involved in aging and development. These targeted studies will be complemented by global gene expression studies to reveal additional genetic pathways that are up or down regulated upon exposure to ascarosides. Follow-up will include additional thermotolerance assays using available mutants or knock-down of affected genes of interest. Results from these investigations will allow us to develop a comprehensive research program targeting specific aging-relevant pathways modulated by ascarosides. It seems likely that many aspects of these pathways are conserved through species, providing incentives for further study of corresponding pathways in other organisms. Moreover, the proposed study could represent a model for the use of endogenous small molecules to probe signaling networks in C. elegans and other organisms. PUBLIC HEALTH RELEVANCE: The pervasive physiological changes associated with aging are reflected in age-dependent increases in the incidence of many diseases, including, diabetes, cancer, neurological disorders, heart disease, and osteoporosis. In nematodes, endogenous compounds called ascarosides have been shown to significantly retard the effects of aging and increase lifespan. The proposed study aims to investigate the biological mechanisms through which the ascarosides increase lifespan in nematodes, which will contribute to our understanding of the causes of aging in humans.

描述（由申请人提供）：在线虫秀丽隐杆线虫中，几组小分子作为内在分子信使控制遗传途径。一组苷类蛔苷最近被证明可以诱导发育停滞（dauer 形成），并且还可以充当性信息素。我们的初步结果表明，蛔苷不仅充当交配信号，而且还强烈影响成虫的寿命和耐热性。因此，蛔苷信号传导提供了发育停滞和衰老之间的直接联系，并提供了一套独特的工具来识别和探测相应的分子途径。该提案的主要目标是确定蛔苷介导的寿命和耐热性增加所涉及的遗传途径。为此，将采用一种新方法采用内源产生的蛔苷的合成样品，该方法将化学基因组学与最近获得的有关这些信号分子生物学作用的知识相结合。使用迄今为止已鉴定的八种蛔苷的合成样品，将确定这些化合物的不同浓度和组合对野生型蠕虫耐热性和寿命的影响。随后，将在额外的耐热性测定中对具有强耐热性或寿命表型的蛔苷或蛔苷组合进行测定，以针对已知参与衰老和发育的关键遗传途径的选择突变体。这些有针对性的研究将得到全球基因表达研究的补充，以揭示接触蛔苷后上调或下调的其他遗传途径。后续工作将包括使用可用突变体或敲除受影响的感兴趣基因进行额外的耐热性测定。这些研究的结果将使我们能够开发一个针对蛔苷调节的特定衰老相关途径的综合研究计划。这些途径的许多方面似乎在物种中是保守的，这为进一步研究其他生物体中的相应途径提供了动力。此外，拟议的研究可以代表使用内源性小分子来探测秀丽隐杆线虫和其他生物体中信号网络的模型。公共卫生相关性：与衰老相关的普遍生理变化反映在许多疾病发病率随年龄增长而增加，包括糖尿病、癌症、神经系统疾病、心脏病和骨质疏松症。在线虫中，一种称为蛔苷的内源性化合物已被证明可以显着延缓衰老并延长寿命。这项研究旨在研究蛔苷延长线虫寿命的生物学机制，这将有助于我们了解人类衰老的原因。