权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
10589758
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
项目类别：
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/10589758
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 Regulatory T-Lymphocyte Research Resolution Role Sampling Shapes Signal Pathway Signal Transduction Structure Surface Systems Development T cell differentiation TLR4 gene Therapeutic Intervention Variant Work 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

项目摘要

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.

项目总结/文摘