Novel Nutrient Functions and Sensing Mechanisms

新颖的营养功能和传感机制

• 批准号: 10535436
• 负责人: MIN HAN
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10535436
• 关键词: Amino Acids; Animals; Behavior; Behavioral; Biochemical; Biological Assay; Biology; Caenorhabditis elegans; Cell Proliferation; Cell Wall; Cellular Metabolic Process; Data; Development; Diet; Enterobactin; Event; Fatty Acids; Genetic; Germ Cells; Glucose; Grant; Health; Human; Immune; Integration Host Factors; Intestines; Investigation; Mammalian Cell; Metabolic; Micronutrients; Modeling; Mus; Nematoda; Nucleotides; Nutrient; Nutritional; Organism; Pathway interactions; Peptidoglycan; Physiological; Physiology; Pyrimidine; Recording of previous events; Research; Role; Siderophores; Signal Transduction; Structure; System; Variant; commensal microbes; deprivation; detection of nutrient; endonuclease; fascinate; innovation; microbiota; novel; nucleotide metabolism; reproductive fitness; response

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.

项目概要/摘要 尽管有着悠久的历史，营养生物学领域仍然面临着众多悬而未决的问题。 与人类健康有关，本提案将探讨其中两个问题。一、营养价值很多 我们饮食中的特定分子，或许多特定细菌代谢物对人类的有益影响 生理学（如共生微生物和宿主动物之间的共生关系所预测）， 仍不清楚。其次，尽管过去几十年在理解方面取得了巨大进步 信号系统感知葡萄糖、氨基酸和其他经过充分研究的营养素的水平以进行调节 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，很大程度上尚未开发。 大约6年前，我们实验室大胆地将主要研究方向转向研究相关问题 营养功能和传感，主要关注尚未开发的脂肪酸变体、核苷酸和 细菌代谢物，使用线虫秀丽隐杆线虫作为主要模型，并在小鼠中进行额外分析 和哺乳动物细胞。一方面，我们开发了创新的检测方法来识别未知的有益物质 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 MIRA 拨款，我们将开展一项 对新发现的 PG 片段的有益作用进行了彻底的研究，这些作用主要是 过去免疫防御研究的主题。通过分析有效的 PG 片段的结构， 对动物生理学各个方面的影响以及相互作用的宿主因素，我们的目标是揭示 细菌PG这一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种新颖的监管体系 剥夺特定脂肪酸和核苷酸变异来调节发育和行为 保护动物生殖健康的活动。特别是，我们在现有 GM R01 补助金下的研究 发现了一条肠道启动的途径，可调节生殖细胞增殖和代谢反应 嘧啶缺乏症。根据 MIRA 的资助，我们将解决围绕以下问题的关键机制问题： 一种不起眼的核酸内切酶的作用，它可以响应核苷酸失衡而增加其表达，以及 在肠道中发挥作用，调节代谢和发育事件。 过去对秀丽隐杆线虫领域的研究表明，这种生物体最适合用于制造新的 代表生物学重要概念进展的发现。凭借有希望的初步数据， MIRA 应用程序中描述的项目具有巨大的潜力，可以做出范式转变的发现， 会影响我们对微生物群产生的分子的营养价值和多样性的理解 营养感应机制。