Ascaroside signaling and aging in Caenorhabditis elegans

描述（由申请人提供）：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Ascarosides，最近已被证明可诱导发育停滞（dauer形成），而且还可作为性信息素。我们的初步研究结果表明，子囊苷不仅作为dauer或交配信号，但也强烈影响成虫寿命和耐热性。因此，Ascaroside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。这项建议的主要目标是确定参与蛔虫苷介导的寿命和耐热性增加的遗传途径。为了这个目的，内源性产生的蛔虫苷的合成样品将采用一种新的方法，该方法将化学基因组学与最近获得的关于这些信号分子的生物学作用的知识相结合。使用迄今为止鉴定的八种Ascarosides的合成样品，将确定这些化合物的各种浓度和组合对野生型蠕虫的耐热性和寿命的影响。随后，将在针对已知参与衰老和发育的关键遗传途径的突变体的选择的另外的耐热性测定中测定具有强耐热性或寿命表型的子囊苷或子囊苷组合。这些有针对性的研究将通过全球基因表达研究来补充，以揭示在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突变体或敲低受影响的感兴趣基因的额外耐热性测定。从这些调查的结果将使我们能够制定一个全面的研究计划，针对特定的衰老相关的途径所调制的蛔虫。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中的相应途径提供了动力。此外，该研究还为利用内源性小分子探针研究C.线虫和其他生物。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的发病率随年龄而增加，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，被称为Ascarosides的内源性化合物已被证明可以显着延缓衰老的影响并延长寿命。这项拟议的研究旨在研究蛔虫苷增加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.