Novel Nutrient Functions and Sensing Mechanisms

新颖的营养功能和传感机制

• 批准号: 10318176
• 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/10318176
• 关键词: Address; 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.

项目摘要/摘要 尽管历史悠久，但营养生物学领域仍在紧密面对许多杰出问题 与人类健康有关，其中两个将在本提案中探讨。首先，许多人的营养价值 我们饮食中的特定分子，或许多特定细菌代谢物对人的有益影响 生理学（如共生微生物和宿主动物之间的共生关系所预测）， 保持不清楚。其次，尽管在过去的几十年中取得了巨大的进步 信号系统感知葡萄糖，氨基酸和其他经过良好研究的养分的水平 各种物理事件，对许多其他特定营养水平响应的机制， 包括某些脂肪酸，核苷酸变体和微量营养素，在很大程度上是意外的。 大约6年前，我们的实验室大胆地将主要研究方向移动到研究与 营养功能和感应，主要集中在探索量不足的脂肪酸变体上，核苷酸和 细菌代谢物，使用线虫C.秀丽隐杆线虫作为主要模型，并在小鼠中进行其他分析 和哺乳动物细胞。在一个方面，我们开发了创新的阿萨斯，以确定未知的有益 细菌代谢产物的影响，包括铁载体肠乳酸和细菌细胞壁成分 肽聚糖（PG），关于动物发育和行为。根据这项Mira赠款，我们将执行 对新发现的PG片段的有益作用的研究主要是 过去的免疫防御研究主题。通过分析潜在PG片段的结构， 对动物生理的各个方面以及相互作用的宿主因素的影响，我们旨在发现 这种引人入胜的新作用的机制。 另一方面，近年来我们的努力发现了四个新颖的​​监管系统 剥夺特定脂肪酸和核苷酸变体以调节发育和行为 保护动物生殖健身的事件。特别是，我们的研究在现有的GM R01赠款下 发现了一种肠道引发的途径，该途径调节了生殖细胞增殖和代谢的反应 减少嘧啶的缺乏。根据此Mira赠款，我们将解决有关的关键机械问题 晦涩的核酸内切酶的作用，该核酸内切酶在响应核苷酸的失衡和 这在肠道中起作用，以调节代谢和发育事件。 秀丽隐杆线虫领域的过去研究表明，这种生物最好用于制作新颖 发现生物学的重要概念进步的发现。有了有希望的初步数据， 此MIRA应用中描述的项目具有巨大的潜力，可以使范式转移发现 将影响我们对微生物群产生的分子和多样性的营养价值的理解 营养感应机制。