Novel Nutrient Functions and Sensing Mechanisms

项目摘要/摘要 尽管有着悠久的历史，营养生物学领域仍然面临着大量的悬而未决的问题。 与人类健康有关的问题，本提案将探讨其中两个问题。首先，许多植物的营养价值 我们饮食中的特定分子，或者许多特定细菌代谢物对人类的有益影响 生理学(根据共生微生物和宿主动物之间的共生关系预测)， 目前仍不清楚。第二，尽管在过去的几十年里，在理解 感知葡萄糖、氨基酸和其他经过充分研究的营养水平的信号系统来调节 各种生理事件，对许多其他特定营养素水平做出反应的机制， 包括某些脂肪酸、核苷酸变体和微量营养素，在很大程度上是未被探索的。 大约6年前，我们实验室大胆地将主要研究方向转移到与 营养功能和传感，主要集中在未被开发的脂肪酸变体、核苷酸和 细菌代谢物，以线虫为主要模型，并在小鼠中进行额外分析 和哺乳动物细胞。一方面，我们开发了创新的分析方法来确定未知的益处 细菌代谢物的影响，包括铁载体肠杆菌素和细菌细胞壁成分 肽聚糖(PG)，对动物发育和行为的影响。根据这笔米拉赠款，我们将进行一项 彻底调查新发现的PG片段的有益作用，这些片段主要是 过去的免疫防御研究课题。通过分析有效的PG片段的结构，他们的 对动物生理的各个方面的影响，以及相互作用的宿主因素，我们的目的是揭示 细菌PG这种令人着迷的新作用的机制。 另一方面，我们近年来的努力发现了四个新的监管系统，这些系统 剥夺特定的脂肪酸和核苷酸变体来调节发育和行为 保护动物生殖健康的活动。特别是，我们在现有GM R01拨款项下进行的研究 发现了一种肠道启动的调节生殖细胞增殖和代谢的途径 到了嘧啶缺乏症。在这笔Mira赠款下，我们将解决有关以下关键机械问题 一种不知名的内切酶的作用，它增加了它的表达，以响应核苷酸不平衡和 它在肠道中起作用，调节新陈代谢和发育事件。 过去对线虫领域的研究表明，这种生物最适合用来制作小说 在生物学概念上取得重大进展的发现。凭借前景看好的初步数据， 这个Mira应用程序中描述的项目具有巨大的潜力，可以做出改变范式的发现， 会影响我们对微生物产生的分子的营养价值和多样性的理解 营养感应机制。

Project Summary/Abstract Despite its long history, the nutrient biology field is still facing a plethora of outstanding questions closely related to human health, two of which will be explored in this proposal. First, the nutrient value of many specific molecules in our diet, or the beneficial impact of many specific bacterial metabolites on human physiology (as predicted by the symbiotic relationship between commensal microbes and host animals), remain unclear. Second, whereas great advances have been made in the last decades on understanding signaling systems that sense the levels of glucose, amino acids and other well-studied nutrients to regulate various physiological events, the mechanisms that respond to the level of many other specific nutrients, including certain fatty acids, nucleotide variants and micronutrients, are largely unexplored. About 6 years ago, our lab boldly moved the major research direction to study problems related to nutrient functions and sensing, focusing mainly on under-explored fatty acid variants, nucleotides and bacterial metabolites, using the nematode C. elegans as the primary model with additional analysis in mice and mammalian cells. In one aspect, we developed innovative assays to identify the unknown beneficial impact of bacterial metabolites, including the siderophore enterobactin and bacterial cell wall components peptidoglycan (PG), on animal development and behaviors. Under this MIRA grant, we will carry out a thorough investigation of the newly discovered beneficial roles of PG fragments that have mainly been the subject of immune defense studies in the past. By analyzing the structure of potent PG fragments, their impacts on various aspects of animal physiology, and the interacting host factors, we aim to uncover the mechanism of this fascinating new role of bacterial PG. In the other aspect, our effort in recent years has uncovered four novel regulatory systems that sense the deprivation of specific fatty acid and nucleotide variants to regulate developmental and behavioral events to protect animals’ reproductive fitness. In particular, our study under the existing GM R01 grant uncovered an intestine-initiated pathway that regulates germ cell proliferation and metabolism in response to pyrimidine deficiency. Under this MIRA grant, we will address critical mechanistic questions surrounding the roles of an obscure endonuclease that increases its expression in response to nucleotide imbalance and that acts in the intestine to regulate metabolic and developmental events. Past research in the C. elegans field has indicated that this organism is best used to make novel discoveries that present important conceptual advances in biology. With promising preliminary data, the projects described in this MIRA application have great potential to make paradigm-shifting discoveries that would impact our understanding of the nutritional value of microbiota-produced molecules and the diversity of nutrient-sensing mechanisms.