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: 10332881
• 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/10332881
• 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.

项目摘要/摘要 人类被人性化的细菌（共同称为微生物组）殖民 调节生理，例如通过潜在的小分子。广泛的努力都确定了至关重要的 微生物组在健康的人类生物学中的作用以及微生物组的组成及其相关的作用 小分子到从自身免疫性疾病到神经系统疾病的疾病。基础 然而 开发微生物组相关疾病的热干预措施。 高通量功能基因组学方法的最新进展是系统地探测功能的 人类和细菌基因的基因，例如基于CRISPR的遗传筛选，现在原理使系统 研究宿主 - 微生物组相互作用的分子机制。为了实现他们的潜力 微生物组生物学，这种系统筛查方法必须在模型系统中实施和验证 概括与宿主 - 微生物组相互作用有关的表型；一旦实施，它们代表 强大的工具来识别产生这些表型的基因。 该建议描述了原代人的功能基因组学方法的发展 树突状细胞，一种模型系统，用于微生物组与人类免疫系统之间的相互作用，以及 这些方法在识别宿主受体和两个类别的身体角色上的应用 细菌糖脂，囊胶多糖和脂多糖。这两个课程都非常丰富 微生物组和个别示例提出了这些分子调节中的中心作用 免疫功能。例如，已知各个囊囊多糖会诱导分化 调节性T细胞和脂多糖是先天免疫细胞的配体，并引起不同的反应 从炎症到免疫抑制。在此提案中，新细菌菌株的发展 糖脂结构中具有控制变化的库与功能基因组学方法相结合 进行糖脂对免疫小球的影响的结构 - 功能分析，并鉴定宿主 介导这些作用的受体和信号通路。这种机制的解剖 宿主微生物组界面处的糖脂信号传导将改善对微生物组在 免疫系统的调节功能和成熟。 本提案中描述的方法将同样适用于研究其他的作用 微生物组衍生的分子，在微生物组疾病中实现的人体受体或单个细菌 菌株。总之，该建议都将提供有关微生物组生物学的新见解，并建立 通常适用于宿主 - 微生物组相互作用的解密机制的方法。