Ascaroside signaling and aging in Caenorhabditis elegans

描述（申请人提供）：在秀丽隐杆线虫中，几组小分子作为内在分子信使控制遗传途径。一组糖苷，即蛔虫苷，最近被证明可以诱导发育阻滞（水形成），而且还可以作为性信息素。我们的初步研究结果表明，蛔虫苷不仅是雄性或交配的信号，而且对成虫的寿命和耐热性有很大的影响。因此，ascaro苷信号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。本提案的主要目标是确定蛔虫苷介导的寿命和耐热性增加的遗传途径。为此，将采用一种新的方法，结合化学基因组学和最近获得的关于这些信号分子的生物学作用的知识，合成内源生产的蛔虫苷样品。利用目前已鉴定的八种蛔虫苷的合成样品，将确定这些化合物的不同浓度和组合对野生型蠕虫的耐热性和寿命的影响。随后，具有强耐热性或寿命表型的蛔虫苷或蛔虫苷组合将在针对已知参与衰老和发育的关键遗传途径的选择突变的额外耐热性试验中进行分析。这些有针对性的研究将得到全球基因表达研究的补充，以揭示暴露于蛔虫苷后上调或下调的其他遗传途径。后续将包括使用可用的突变体或感兴趣的受影响基因的敲除进行额外的耐热性测定。这些研究的结果将使我们能够制定一个针对蛔虫苷调节的特定衰老相关途径的综合研究计划。似乎这些途径的许多方面在物种中是保守的，这为进一步研究其他生物的相应途径提供了动力。此外，该研究可能代表了一种利用内源性小分子探测秀丽隐杆线虫和其他生物信号网络的模型。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的年龄依赖性增加上，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，被称为蛔虫苷的内源性化合物已被证明可以显著延缓衰老的影响并延长寿命。本研究旨在探讨蛔虫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。

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.