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

项目总结-一个小的贡献，一个大的问题：瘦素信号和肠脑轴 该研究旨在解决瘦素受体（LEP-R）复合物的自组装控制能量 体内平衡及其对肠道微生物群组成影响。瘦素及其受体被认为是 营养状况与肠道微生物组之间的联系，尽管这种激素及其作用是否 尽管它在人类健康中发挥着重要作用， 人瘦素受体（hLEP-R）复合物的分子细节仍然不清楚。我们的跨学科 利用分子动力学（MD）模拟，体外生物物理表征， 在细胞测定和使用黑腹果蝇（D. melanogaster）的体内实验中，作为我们的遗传模型 系统使我们的研究处于一个独特的位置，以建立在我们以前在人类瘦素（hLEP）的发现。 因此，在本发明中， 在动物王国中保存下来的基因研究得很少。 利用哺乳动物研究的背景来研究D. 黑腹动物来测试我们的假设，如果LEP信号是一个共享的字符之间的动物。年的目标 一个是生产转基因果蝇，解决骨干分配，并找到冷冻的实验条件， 使用转移电子显微镜（TEM）在UH的MICRO核心进行LEP-R复合物的EM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 行为我们将确定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影响。在这个项目中，我们将 表征人LEP（hLEP）和hLEP-R，阐明LEP信号传导的分子细节，以确定LEP的分子结构。 研究饮食，微生物群和LEP-R之间的联系。

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.