Novel Nutrient Functions and Sensing Mechanisms

新颖的营养功能和传感机制

• 批准号: 10799400
• 负责人: MIN HAN
• 金额: $ 21.99万
• 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/10799400
• 关键词: Address; Agonist; Amino Acids; Animals; Antibiotics; Applications Grants; Bacteria; Behavior; Binding; Caenorhabditis elegans; Cardiovascular Diseases; Cell Wall; Cells; Complex; Data; Development; Disaccharides; Disease; Enterobactin; Epithelial Cells; Equipment; Event; Fatty Acids; Fibroblasts; Funding; Genetic Screening; Genus Hippocampus; Goals; Grant; Health; Homeostasis; Human; Intestines; Mammalian Cell; Measures; Medical; Metabolic Diseases; Mitochondria; Mus; Nematoda; Neurodegenerative Disorders; Nucleotides; Nutrient; Oxidative Phosphorylation; Oxidative Stress; Patients; Peptidoglycan; Physiological; Physiology; Property; Repression; Research; Respiration; Role; Siderophores; Tissues; cell type; commensal microbes; detection of nutrient; human disease; innovation; intestinal epithelium; mitochondrial dysfunction; novel; response

Project Summary In our original proposal for the R35 grant application, we described the two major goals of the research in the field of nutrient function and sensing. One is to discover nutrient value, or the benefits, of specific bacteria-produced metabolites on human physiology, which had been predicted by the symbiotic relationship between commensal microbes and host animals. The second goal was to uncover novel mechanisms that regulate specific physiological events in response to deficiency of specific nutrients that include fatty acids, nucleotides, and amino acids. These studies address fundamental questions that are closely related to human health. For this "Supplement Application" that aims to acquire funding for purchasing a piece of equipment to measure oxidative respiration in animal cells, the research strategy mainly focuses on the first goal. Using innovative genetic screens in the nematode C. elegans, we have identified unexpected beneficial roles of certain bacterial metabolites, including the siderophore enterobactin and bacterial cell wall components peptidoglycan muropeptides, on animal development and behaviors. Supported by the R35 grant and its R01 precursor grant, we have made exciting progress in understanding the mechanisms underlying these novel functions. Both molecules enter the mitochondria of host intestinal cells, bind to ATP synthase, and promote basic mitochondrial functions. In the case of muropeptides, we have found that beneficial molecules are disaccharide muropeptides containing a short AA chain, and they enter mitochondria of intestinal cells to repress oxidative stress. Strikingly, muropeptides execute this role by binding to multiple subunits of ATP synthase, which consequently stabilizes the complex and promotes its activity. This finding defined the first agonist of the ATP synthase. More recent studies using cultured human intestinal epithelial cells, fibroblasts from a disease patient, and mice treated with antibiotics have clearly indicated the roles of muropeptides in promoting oxidative phosphorylation and suppressing oxidative stress in mammalian cells. In the next several years, we will continue to expand the analyses on potent muropeptides to understand its structural property, its role in promoting oxidative phosphorylation in different mammalian tissues, and its potential effect in suppressing mitochondrial dysfunction in disease cells and mice. Such studies are of high medical significance, as mitochondrial dysfunction is well known to be associated with a broad range of human diseases including major neurodegenerative, cardiovascular, and metabolic diseases. We also plan to explore potential roles of other metabolites and nutrient sensing mechanisms in mitochondrial homeostasis. Having a Seahorse Analyzer to examine oxidative respiration would greatly facilitate these proposed studies on mitochondrial functions.

项目摘要 在我们针对R35赠款申请的最初建议中，我们描述了研究的两个主要目标 在养分功能和感测的领域。一种是发现特定的营养价值或收益 细菌产生的人类生理代谢产物，这是由共生预测的 共生微生物与宿主动物之间的关系。第二个目标是揭示小说 根据特定营养素的不足，调节特定生理事件的机制 包括脂肪酸，核苷酸和氨基酸。这些研究解决了基本问题 与人类健康密切相关。对于这种旨在获得资金的“补充申请” 购买一件设备以测量动物细胞中的氧化呼吸，研究策略 主要关注第一个目标。在线虫C.秀隐杆线虫中使用创新的遗传筛选，我们有 确定了某些细菌代谢产物的意外有益作用，包括铁载体肠actin 和细菌细胞壁成分肽聚糖糊状物，关于动物的发育和行为。 在R35赠款及其R01前体赠款的支持下，我们在理解方面取得了令人兴奋的进步 这些新功能的基础机制。这两个分子都进入宿主肠道的线粒体 细胞，与ATP合酶结合，并促进基本的线粒体功能。就穆洛肽而言，我们 已经发现有益的分子是含有短AA链的二糖糊状剂，并且它们是 输入线粒体的肠细胞以抑制氧化应激。令人惊讶的是，Muropeptides执行此角色 通过与ATP合酶的多个亚基结合，从而稳定复合物并促进 它的活动。这一发现定义了ATP合酶的第一个激动剂。最近使用培养的研究 人肠上皮细胞，疾病患者的成纤维细胞和用抗生素治疗的小鼠具有 清楚地表明了杂肽在促进氧化磷酸化和抑制中的作用 哺乳动物细胞中的氧化应激。在接下来的几年中，我们将继续扩展分析 有效的杂肽了解其结构特性，其在促进氧化磷酸化中的作用 不同的哺乳动物组织及其在抑制线粒体功能障碍中的潜在影响 细胞和小鼠。这样的研究具有很高的医学意义，因为线粒体功能障碍是众所周知的 与广泛的人类疾病有关，包括主要神经退行性，心血管， 和代谢疾病。我们还计划探索其他代谢物和营养感应的潜在作用 线粒体稳态的机制。拥有海马分析仪检查氧化呼吸 将极大地促进有关线粒体功能的这些提出的研究。