Genetic basis of diet-dependent responses across the lifespan

项目总结： 线虫通过紧张对食物供应、环境条件和细菌饮食的变化做出反应 感觉信息和协调的行为、生理和代谢反应的系统整合12， 13、14.线虫的实验室和自然环境与现有的细菌截然不同-- 实验室环境依赖于大肠杆菌的单一培养，而自然环境使线虫暴露于 种类繁多的细菌，包括类杆菌、变形杆菌和放线杆菌1，2。我最近 已发表的研究利用了在线虫自然环境和实验室环境中发现的细菌饮食 并提供对生理和转录签名变化的全面评估 为了简单地改变细菌，在3号上繁殖了蠕虫。据我所知，这是第一篇 面对面的比较，展示了自然环境如何与之不协调地控制生理 然而，我意识到这项研究只是理解 饮食暴露与生活史特征之间的多重关系。这项提案的首要目标是 揭示复杂食物决策的新机制，阐明潜在的遗传基础 一生中对饮食的依赖反应。通过两种主要方法，我计划利用 线虫的模型和研究两个不同的生理属性，发育和食物 饮食中暴露于促进寿命的细菌可能会对选择产生不同的影响。第一个目标将是 通过制定无偏见的食物选择，确定在两种细菌饮食之间做出决定的神经回路 化验(1a)。通过使用这些分析，我计划识别与组合有关的嗅觉通路 神经元消融和基因突变(1b)。最后，我将研究嗅觉的这些突变是如何 途径将影响线虫的适应能力和汇聚的多个生理方面 衰老和寿命(1c)。我的第二个目标是依靠遗传学研究细菌饮食是如何控制正常的 发展的进程。我计划通过鉴定产生的发育缓慢的突变体来实现这一目标 通过甲磺酸乙酯筛选，以揭示发育时序的新的遗传调节因子(2a)。 由于参与饮食反应的信号通路高度保守，这些研究将揭示新的 洞察饮食对健康长寿的影响，并激励未来将食物用作营养食品的研究 以对抗衰老和疾病的发作。

Project Summary: C. elegans respond to changes in food availability, environmental conditions, and bacterial diets through nervous system integration of sensory information and coordinated behavioral, physiological, and metabolic responses12, 13, 14. The laboratory and natural environments of C. elegans differ drastically in the bacterium present – the laboratory environment relies on monocultures of E. coli, while the natural environment exposes C. elegans to a wide variety of bacterial species including Bacteroidetes, Proteobacteria, and Actinobacteria1, 2. My recently published study takes advantage of bacterial diets found in both C. elegans natural and laboratory environments and provides a comprehensive assessment of changes in physiology and transcriptomic signatures as a result to simply changing the bacteria diet worms were propagated on3. To my knowledge, this paper was the first head-to-head comparison demonstrating how the natural environment controls physiology incongruously to that of the laboratory environment, however, I realized that this study is just the beginning of understanding the multiplexed relationship between dietary exposure and life history traits. The overarching goal of this proposal is to reveal novel mechanisms of the complex food-based decision making to elucidate the underlying genetic basis of diet-dependent responses across the lifespan. With two main approaches, I plan to take advantage of the amenable C. elegans model and examine how two distinct physiological attributes, development and food choice, can be differentially impacted by dietary exposure to lifespan-promoting bacteria. The first aim will be to identify the neurocircuitry involved in deciding between two bacterial diets by developing unbiased food choice assays (1a). With the use of these assays, I plan to identify the olfactory pathways involved with a combination of neuronal ablation and genetic mutants (1b). Finally, I will examine how these mutations in the olfactory pathways will influence C. elegans adaptive capacity and the multiple aspects of physiology that converge upon aging and lifespan (1c). My second aim relies on genetics to examine how bacterial diet controls normal progression of development. I plan to approach this aim by identifying developmentally slow mutants generated by an ethyl methanesulfonate screen in order to reveal novel genetic regulators of developmental timing (2a). Due to the high conservation of signaling pathways involved in dietary response, these studies will reveal new insights into impacts diet has on health on longevity and stimulate future studies to use food as a nutraceutical to combat the onset of aging and diseases.