Deciphering the logic of glycolipid signaling at the host-microbiome interface

破译宿主-微生物组界面糖脂信号传导的逻辑

• 批准号: 10392518
• 负责人: Marco Jost
• 金额: $ 24.9万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-16 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10392518
• 关键词: Adaptive Immune System; Affect; Agonist; Antigen-Presenting Cells; Antigens; Attenuated; Autoimmune Diseases; Bacteria; Bacterial Antigens; Bacterial Genes; Bacteroides; Bacteroides fragilis; Bacteroides thetaiotaomicron; Benchmarking; Biological Models; Biology; CD14 Antigen; CRISPR/Cas technology; Cell surface; Cells; Chemicals; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Data; Dendritic Cell Pathway; Dendritic Cells; Development; Disease; Dissection; Genes; Genetic; Genetic Screening; Genetic Transcription; Genomic approach; Glycolipids; Human; Human Biology; Human Microbiome; Immune; Immune response; Immune system; Immunosuppression; Individual; Inflammation; Inflammatory; Innate Immune System; Interleukin-10; Knock-out; Knowledge; Libraries; Ligands; Link; Lipids; Lipopolysaccharides; Logic; Measures; Mediating; Mentors; Methods; Microbe; Modeling; Modification; Molecular; Pathway interactions; Phase; Phenotype; Physiological; Physiology; Polysaccharides; Predisposition; Production; Receptor Signaling; Regulatory T-Lymphocyte; Research; Resolution; Role; Sampling; Shapes; Signal Pathway; Signal Transduction; Structure; Sum; Surface; Systems Development; T cell differentiation; TLR4 gene; Therapeutic Intervention; Variant; Work; base; cell mediated immune response; cytokine; exposed human population; functional genomics; genomic tools; gut microbes; host microbiome; host microbiota; immune function; immune system function; immunoregulation; improved; insight; knockout gene; member; microbiome; microbiome composition; microbiota; mouse model; nervous system disorder; programs; receptor; response; screening; small molecule; symbiont; targeted sequencing; therapeutic development; therapy development; tool

Project Summary/Abstract Humans are densely colonized with symbiotic bacteria – collectively referred to as the microbiome – that modulate physiology, for example through potent small molecules. Extensive efforts have both identified crucial roles of the microbiome in healthy human biology and linked composition of the microbiome and its associated small molecules to diseases ranging from autoimmune diseases to neurological disorders. The underlying molecular mechanisms of host-microbiome interactions, however, are largely undefined, impeding the development of therapeutic interventions for microbiome-associated diseases. Recent advances in high-throughput functional genomics methods to systematically probe the functions of human and bacterial genes, such as CRISPR-based genetic screens, now in principle enable systematic studies into the molecular mechanisms of host-microbiome interactions. To achieve their potential for microbiome biology, such systematic screening methods must be implemented and validated in model systems that recapitulate phenotypes relevant to host-microbiome interactions; once implemented, they represent powerful tools to identify genes involved in producing these phenotypes. This proposal describes the development of functional genomics approaches for primary human dendritic cells, a model system for interactions between the microbiome and the human immune system, and the application of these approaches to the identification of host receptors and physiological roles of two classes of bacterial glycolipids, capsular polysaccharides and lipopolysaccharides. Both classes are highly abundant in the microbiome and individual examples have suggested central roles for these molecules in modulating immune function. For example, individual capsular polysaccharides are known to induce differentiation of regulatory T-cells, and lipopolysaccharides are ligands for innate immune cells and elicit varying responses ranging from inflammation to immunosuppression. In this proposal, the development of new bacterial strain libraries with controlled variations in glycolipid structure is combined with functional genomics approaches to conduct structure-function analyses of the effects of glycolipids on immune cells and to identify the host receptors and signaling pathways that mediate these effects. This dissection of the mechanisms underlying glycolipid signaling at the host-microbiome interface will improve understanding of the role of the microbiome in modulating function and maturation of the immune system. The approaches described in this proposal will be similarly applicable to study the roles of other microbiome-derived molecules, human receptors implicated in microbiome diseases, or individual bacterial strains. Altogether, this proposal will both provide new insight into the biology of the microbiome and establish generally applicable approaches to decipher mechanisms of host-microbiome interactions.

项目概要/摘要 人类密集地居住着共生细菌——统称为微生物组—— 调节生理学，例如通过有效的小分子，广泛的努力都发现了关键的作用。 微生物组在健康人类生物学中的作用以及微生物组及其相关的组成 小分子到从自身免疫性疾病到神经系统疾病的疾病。 然而，宿主-微生物组相互作用的分子机制在很大程度上尚不明确，这阻碍了 开发微生物组相关疾病的治疗干预措施。 系统探测功能的高通量功能基因组学方法的最新进展 人类和细菌基因的分析，例如基于 CRISPR 的遗传筛选，现在原则上可以实现系统化 研究宿主-微生物组相互作用的分子机制，以发挥其潜力。 微生物组生物学，这种系统筛选方法必须在模型系统中实施和验证 一旦实施，它们就会概括与宿主-微生物组相互作用相关的表型； 识别参与产生这些表型的基因的强大工具。 该提案描述了初级人类功能基因组学方法的发展 树突状细胞，微生物组和人类免疫系统之间相互作用的模型系统，以及 这些方法在鉴定宿主受体和两类生理作用方面的应用 细菌糖脂、荚膜多糖和脂多糖都非常丰富。 微生物组和个别例子表明这些分子在调节中发挥着核心作用 例如，已知单个荚膜多糖可诱导免疫功能的分化。 调节性 T 细胞和脂多糖是先天免疫细胞的配体，可引发不同的反应 从炎症到免疫抑制，在该提案中，开发了新的细菌菌株。 糖脂结构受控变异的文库与功能基因组学方法相结合 对糖脂对免疫细胞的影响进行结构功能分析并识别宿主 介导这些效应的受体和信号通路。 宿主-微生物组界面的糖脂信号传导将增进对微生物组在 调节免疫系统的功能和成熟。 本提案中描述的方法同样适用于研究其他领域的作用 微生物组衍生分子、与微生物组疾病有关的人类受体或单个细菌 总而言之，该提案将提供对微生物组生物学的新见解并建立。 破译宿主-微生物组相互作用机制的普遍适用的方法。