Genetic basis of diet-dependent responses across the lifespan

整个生命周期饮食依赖性反应的遗传基础

• 批准号: 10535264
• 负责人: Nicole Lynn Stuhr
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-11 至 2023-08-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10535264
• 关键词: Ablation; Address; Aging; Bacteria; Bacteroidetes; Behavior; Behavioral; Biological Assay; Caenorhabditis elegans; Choice Behavior; Complex; Computational Biology; Consumption; Decision Making; Development; Diet; Dietary History; Disease; Eating; Energy Intake; Environment; Escherichia coli; Ethyl Methanesulfonate; Excision; Exposure to; Food; Food Contamination; Foundations; Future; Genetic; Genomics; Goals; Health; Human; Knowledge; Laboratories; Lead; Longevity; Maintenance; Mediating; Metabolic; Methylobacterium; Modeling; Modification; Molecular Biology; Mutation; Nervous system structure; Neurobiology; Neurons; Nutraceutical; Olfactory Pathways; Organism; Paper; Pathway interactions; Phenotype; Physiological; Physiology; Proteobacteria; Publishing; Research; Shapes; Signal Pathway; Societies; Source; Sphingomonas; Standardization; Training; Variant; Xanthomonas; base; combat; dietary; dietary control; experience; good diet; head-to-head comparison; healthspan; healthy aging; holistic approach; insight; life history; mutant; neural circuit; novel; nutritional genomics; phrases; preference; response; sensory integration; species difference; trait; transcriptomics

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.

项目摘要： 秀丽隐杆线虫通过神经响应食物可用性，环境状况和细菌饮食的变化 感官信息和协调行为，物理和代谢反应的系统集成12， 13，14。在存在的细菌中，秀丽隐杆线虫的实验室和自然环境的实验室和自然环境 - 实验室环境依靠大肠杆菌的单一培养，而自然环境则暴露于秀丽隐杆线虫 各种各样的细菌种类，包括细菌植物，蛋白质细菌和静脉细菌1，2。我最近 发表的研究利用了秀丽隐杆线虫自然和实验室环境中发现的细菌饮食 并因此对生理学和转录组签名的变化进行了全面评估 简单地改变细菌饮食蠕虫的繁殖3。据我所知，本文是第一篇 面对面的比较证明了自然环境如何与此控制不一致 但是，在实验室环境中，我意识到这项研究只是理解的开始 饮食暴露与生活历史特征之间的多重关系。该提议的总体目标是 揭示基于食物的复杂决策的新机制，以阐明基本的遗传基础 整个生命周期的饮食依赖性反应。通过两种主要方法，我计划利用 可染色的秀丽隐杆线虫模型，并检查两个不同的物理属性，开发和食物如何 选择，可能会因饮食中促进生命周期的细菌而受到差异影响。第一个目标是 通过开发无偏食的食物选择，确定在两种细菌饮食之间决定的神经通路 测定（1A）。通过使用这些评估，我计划确定与组合相关的嗅觉途径 神经元消融和基因突变体（1b）。最后，我将检查嗅觉中的这些突变如何 途径将影响秀丽隐杆线虫的自适应能力和融合的生理学多个方面 衰老和寿命（1C）。我的第二个目的依靠遗传学来检查细菌饮食如何控制正常 发展的进展。我计划通过识别产生的发育缓慢的突变体来实现这一目标 通过甲基磺酸乙酯筛选，以揭示发育时机的新遗传调节剂（2a）。 由于饮食反应中涉及的信号传导途径的高保守性，这些研究将揭示新的 对饮食对寿命的健康影响的见解，并刺激将来的研究以食物为营养 打击衰老和疾病的发作。