Gatekeeping glycan metabolism in the human gut microbiome

人类肠道微生物组中的聚糖代谢把关

基本信息

批准号：
10737225
负责人：
ERIC JOHN SUNDBERG
金额：
$ 38.61万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10737225
关键词：
Address Asparagine Bacteria Bacterial Antibiotic Resistance Bacteroidetes Binding Proteins Biochemical Carbohydrates Cell surface Collaborations Colon Carcinoma Complex Consensus Development Diet Dietary Fiber Digestion Disease Disparate Employment Endoglycosidases Energy-Generating Resources Environment Enzymes Event Exhibits Exoglycosidases Gatekeeping Genes Genetic Genetic Techniques Glycobiology Glycoproteins Goals Growth Health Human Hydrolysis Individual Inflammatory Inflammatory Bowel Diseases Intestines Kinetics Link Mannose Mass Spectrum Analysis Measures Membrane Metabolism Methods Microbe Molecular Mucins Mucous Membrane Nutrient Obesity Pathway interactions Physiology Play Polysaccharides Process Proteins Research Role Specificity Structure Substrate Specificity Work bacterial metabolism biophysical techniques design dysbiosis gut bacteria gut microbes gut microbiome gut microbiota human disease immunoregulation improved innovation link protein member microbial community microbiota microorganism novel novel therapeutics nutrient absorption pathogen pathogenic bacteria sensor superresolution microscopy

项目摘要

The overall goal of this application is to define mechanisms of glycan metabolism by bacteria inhabiting the human gut microbiome so as to establish novel therapeutic pathways to manipulating the composition of the gut microbial community to treat myriad human diseases. The gut microbiota has a profound effect on human health and physiology, providing the host benefits such as modulation of immune development, inhibition of pathogen colonization, digestion of dietary fibers and absorption of nutrients. Abnormalities in microbiota composition, or dysbiosis, however, have been implicated in numerous and diverse disease states. A critical variable that dictates the composition and physiology of the microbiota is the influx of glycans into the intestine, mostly from diet and host mucosal secretions. Given the broad diversity of glycans that enter and exist in the gut, microorganisms must possess varied and efficient strategies for competing for these nutrients, on which they depend as a critical energy source. Despite the prominence of glycans in the human intestine and its documented role in controlling important aspects of health and disease, the molecular mechanisms of glycan breakdown and import employed by gut microbes remain poorly understood. This severely limits our ability to build an intellectual framework for the design of methods and molecules with which to remodel the composition of the gut microbiota in order to improve human health – for instance, to favor commensal over pathogenic bacteria or to limit the growth of inflammatory or antibiotic-resistant bacteria. Here, we propose mechanistic studies using biochemical, biophysical and genetic techniques to define pathways employed by gut microbes for the degradation and import of various glycans, and to determine the structures and functions of key enzymes that release glycans, as well as their interactions and functional cooperation with proteins that capture these released glycans. This work is significant because it addresses molecular mechanisms involved in the major human health burden of dysbiosis. The proposed studies are innovative both technically and conceptually – from the development and employment of novel mass spectrometry-based methods for measuring the specificity and kinetics of protein deglycosylation to the hypotheses that a single bacterium can express multiple enzymes with the same glycan specificity in order to survive in distinct environments and that glycan-hydrolyzing enzymes have evolved to become a new class of cell surface glycan-binding proteins. The research plan will be accomplished through ongoing and new collaborations between the Sundberg, Koval and Mallagaray labs, who bring non-overlapping, complementary and synergistic strengths in structural glycobiology and super-resolution microscopy, resulting in a collaborative team ideally suited to this project.

该应用的总体目的是通过居住的细菌来定义聚糖代谢的机制人肠道微生物组，以建立新型的热途径来操纵肠的组成微生物社区治疗无数人类疾病。肠道菌群对人类健康有深远的影响和生理学，提供宿主的益处，例如免疫发育的调节，抑制病原体定植，饮食纤维的消化和滥用营养。微生物群组成异常，或然而，在许多多样化的疾病状态下，疾病已经隐含了营养不良。一个关键变量杀菌的决定和生理学是聚糖对肠的影响，主要来自饮食和宿主粘膜分泌物。鉴于进入肠道并存在的聚糖多样性，微生物必须具有各种有效的策略来争夺这些营养素，它们在其上 depite在人类肠道及其记录的肠道中的突出在控制健康和疾病的重要方面的作用，聚糖分解的分子机制和由肠道微生物进口仍然很少了解。这严重限制了我们建立智力的能力设计和分子设计的框架，用于重塑肠道菌群的组成为了改善人类健康 - 例如，为了偏爱致病细菌或限制炎症或抗生素耐药菌的生长。在这里，我们提出了使用生化的机械研究生物物理和遗传技术来定义肠道微生物携带的途径降解和进口各种聚糖，并确定释放聚糖的关键酶的结构和功能随着它们与捕获这些释放的聚糖的蛋白质的相互作用和功能合作。这项工作是意义重大，因为它解决了与营养不良的主要人类健康燃烧有关的分子机制。拟议的研究在技术上和概念上都是创新的 - 从发展和就业基于新型质谱法的新方法，用于测量蛋白质脱糖基化的特异性和动力学假设单个细菌可以以相同的聚糖特异性表达多种酶为了在不同的环境中生存，聚糖 - 水解酶已经发展为新的类别细胞表面聚糖结合蛋白。研究计划将通过持续的新 Sundberg，Koval和Mallagaray Labs之间的合作，他们带来了不重叠的完整性结构性糖生物学和超分辨率显微镜的协同优势，导致协作团队非常适合该项目。