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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.

本申请的总体目标是定义由栖息在微生物中的细菌进行的聚糖代谢的机制。从而建立新的治疗途径来操纵肠道的组成微生物群落来治疗无数的人类疾病。肠道微生物群对人类健康有着深远的影响和生理学，为宿主提供益处，例如调节免疫发育、抑制病原体定植、膳食纤维消化和营养素吸收。微生物群组成减少，或然而，生态失调与许多不同的疾病状态有关。一个关键的变量，决定微生物群的组成和生理学的是聚糖流入肠道，主要来自饮食和宿主粘膜分泌物。鉴于进入和存在于肠道中的聚糖的广泛多样性，微生物必须拥有各种有效的竞争这些营养素的策略，作为一种重要的能源。尽管聚糖在人类肠道中的重要性及其记录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，对肠道微生物利用输入仍然知之甚少。这严重限制了我们建立一个知识分子的能力。用于设计方法和分子的框架，以重塑肠道微生物群的组成为了改善人类健康-例如，有利于益生菌而不是致病菌，或者限制炎症或抗药性细菌的生长。在这里，我们建议使用生物化学，生物物理和遗传技术，以确定肠道微生物用于降解和输入的途径以及确定释放聚糖的关键酶的结构和功能，因为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。这项工作是重要的是，它解决了生态失调的主要人类健康负担所涉及的分子机制。所提出的研究在技术和概念上都是创新的-从发展和就业用于测量蛋白质去糖基化的特异性和动力学的基于质谱的新方法单一细菌可以表达具有相同聚糖特异性的多种酶，在不同的环境中生存，聚糖水解酶已经进化成为一类新的细胞表面聚糖结合蛋白。该研究计划将通过正在进行的和新的 Sundberg，Koval和Mallagaray实验室之间的合作，他们带来了非重叠，互补和协同优势，在结构糖生物学和超分辨率显微镜，从而在一个合作团队非常适合这个项目。