A Small Contribution to a Large Problem: Leptin-Signaling and the Gut-Brain Axis

大问题的小贡献：瘦素信号传导和肠脑轴

• 批准号: 10712777
• 负责人: Ellinor Haglund
• 金额: $ 21.98万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712777
• 关键词: Affect; Animals; Automobile Driving; Behavior; Binding; Biological; Biological Models; Biology; Cellular Assay; Characteristics; Chronic; Complex; Cryoelectron Microscopy; Cytokine Receptors; Diabetes Mellitus; Diet; Drosophila genus; Drosophila melanogaster; Electron Microscopy; Electron Transport; Environment; Enzymes; Genetic Models; Germ-Free; Glean; Goals; Health; Homeostasis; Hormones; Human; In Vitro; Interdisciplinary Study; Leptin; Link; Molecular; Molecular Conformation; Nutritional status; Obesity; Phenotype; Play; Positioning Attribute; Post-Translational Protein Processing; Property; Proteins; Regulation; Research; Role; Signal Transduction; Site; Stress; Structure; Testing; Transgenic Organisms; Transmission Electron Microscopy; Vertebral column; biophysical properties; comparison control; diet-induced obesity; experimental study; fly; glycosylation; gut microbiome; gut microbiota; gut-brain axis; host microbiota; human disease; in vivo; insight; interdisciplinary approach; knock-down; leptin receptor; microbial composition; microbiome; microbiome composition; microbiota; molecular dynamics; obesogenic; protein structure; receptor; receptor function; response; self assembly; stoichiometry; targeted treatment

PROJECT SUMMARY - A small contribution to a large problem: Leptin-signaling and the gut-brain axis The proposed research aims to solve the self-assembly of the leptin receptor (LEP-R) complex controlling energy homeostasis and its influence on gut microbiota composition. Leptin and its receptor have been proposed to be the link between nutritional status and the gut microbiome, although whether this hormone and its action is Despite its important role in human health, the molecular details of the human leptin receptor (hLEP-R) complex remain elusive. Our interdisciplinary approach utilizing a combination of molecular dynamic (MD) simulations, in vitro biophysical characterization, in cell assays, and in vivo experiments using Drosophila melanogaster (D. melanogaster) as our genetic model system puts our research in a unique position to build on our previous discoveries in human leptin (hLEP). Thus, conserved across the animal kingdom is poorly studied. taking advantage of the background developed in mammalian research to study the phenotype of D. melanogaster to test our hypothesis if LEP-signaling is a shared character among animals. The aim for year one is to produce transgenic flies, solve the backbone assignments, and find experimental conditions for Cryo- EM experiments for the LEP-R complexes using transfer electron microscopy (TEM) at the MICRO core at UH. The long-term aim is to understand LEP-signaling and the role of the diet and microbiome in driving the signaling behavior. We will define the signaling-complex's molecular details, effects of the gut microbiota’s secreted enzymes on this complex, and, reciprocally, leptin’s impact on microbiome composition. In this project, we will characterize human LEP (hLEP) and hLEP-R’s, elucidating the molecular details of LEP-signaling to set the stage for studies of the links among diet, microbiota, and LEP-R.

项目摘要 - 对一个大问题的小贡献：瘦素信号传导和肠脑轴 拟议的研究旨在解决控制能量的瘦素受体（LEP-R）复合物的自组装 稳态及其对肠道微生物群组成的影响。瘦素及其受体被认为是 营养状况和肠道微生物群之间的联系，尽管这种激素及其作用是否 尽管它对人类健康具有重要作用， 人类瘦素受体（hLEP-R）复合物的分子细节仍然难以捉摸。我们的跨学科 方法结合分子动力学 (MD) 模拟、体外生物物理表征、 使用果蝇 (D. melanogaster) 作为我们的遗传模型进行细胞测定和体内实验 系统使我们的研究处于独特的地位，以我们之前在人类瘦素 (hLEP) 方面的发现为基础。 因此， 整个动物界的保守性研究很少。 利用哺乳动物研究的背景来研究 D. 黑腹果蝇来检验我们的假设，LEP 信号是否是动物之间的共同特征。年度目标 一是生产转基因果蝇，解决主干任务，并找到冷冻实验条件 使用转移电子显微镜 (TEM) 在夏威夷大学的 MICRO 核心进行 LEP-R 复合物的电磁实验。 长期目标是了解 LEP 信号传导以及饮食和微生物组在驱动信号传导中的作用 行为。我们将定义信号复合物的分子细节、肠道微生物群分泌的影响 酶对这种复合物的影响，以及瘦素对微生物组组成的相互影响。在这个项目中，我们将 表征人类 LEP (hLEP) 和 hLEP-R，阐明 LEP 信号传导的分子细节，以设定 研究饮食、微生物群和 LEP-R 之间联系的阶段。