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.

项目总结/摘要 尽管营养生物学有着悠久的历史，但它仍然面临着许多悬而未决的问题 与人类健康有关，本提案将探讨其中两个问题。一、营养价值多 我们的饮食中的特定分子，或许多特定的细菌代谢物对人类的有益影响， 生理学（如通过寄生微生物和宿主动物之间的共生关系所预测的）， 仍然不清楚。其次，尽管在过去几十年里， 信号系统，感知葡萄糖，氨基酸和其他研究充分的营养素的水平，以调节 各种生理事件，对许多其他特定营养素水平作出反应的机制， 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移到研究与 营养功能和传感，主要集中在未开发的脂肪酸变体，核苷酸和 细菌代谢产物，利用线虫C.线虫作为主要模型，在小鼠中进行额外分析 和哺乳动物细胞。一方面，我们开发了创新的测定方法来鉴定未知的有益的 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赠款，我们将开展一项 彻底调查新发现的有益作用的PG片段，主要是 免疫防御研究的课题。通过分析有效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这一迷人的新作用的机制。 另一方面，我们近年来的努力发现了四种新的调控系统， 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，我们根据现有的GM R 01补助金进行的研究 发现了一种由精氨酸启动的途径，调节生殖细胞的增殖和代谢， 嘧啶缺乏症根据这项MIRA赠款，我们将解决关键的机械问题， 一种模糊的核酸内切酶的作用，这种核酸内切酶在响应核苷酸不平衡时增加其表达， 它在肠道中起调节新陈代谢和发育的作用。 过去在C. elegans领域已经表明，这种生物体最好用于制造新的 在生物学上提出重要概念的发现。有了有希望的初步数据， MIRA申请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的理解， 营养感应机制。