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Decode and design T cell induction by a complex gut microbial community

复杂肠道微生物群落解码和设计 T 细胞诱导

基本信息

批准号：
10572613
负责人：
Kazuki Nagashima
金额：
$ 13.21万
依托单位：
STANFORD 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：
2023-07-11 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10572613
关键词：
Advisory Committees Anti-Inflammatory Agents Antigens Autoimmune Diseases Award B-Lymphocytes Bacteria Bacterial Antigens Biological CD4 Positive T Lymphocytes Cell Communication Cell Line Cell physiology Cells Cellular biology Coculture Techniques Colitis Communicable Diseases Communities Complement Complex Disease Dropout Drops Ecosystem Epitopes Escherichia coli Feces Gene Cluster Germ-Free Goals Human Human Microbiome Hybridomas Immune Immune response Immune system Immunologics Immunology Individual Inflammatory Inflammatory Bowel Diseases Interleukin-10 Knowledge Libraries Logic MHC antigen Malignant Neoplasms Mentors Mentorship Metabolic Diseases Metagenomics Methods Microbe Microbiology Modeling Molecular Molecular Biology Mus Paper Pattern Peptide Library Phenotype Physiological Regulatory T-Lymphocyte Reporting Research Resolution Role Shotguns Signal Transduction Site Stimulus T cell response T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets TCR Activation Taxonomy Technology Testing Therapeutic Therapeutic Effect Time Training Variant Work adaptive immune response antigen-specific T cells bacterial community bacterial genetics cancer therapy design fecal transplantation genetic signature gut microbiome gut microbiota host-microbe interactions immune function immunoreaction immunoregulation improved in vivo insight medical specialties member microbial microbial community microbiome microbiome components microbiota mouse model neglect new technology novel therapeutic intervention novel therapeutics predictive tools programs rational design response screening single cell technology three dimensional structure tool

项目摘要

Project Summary/Abstract Immune modulation holds tremendous promise for the treatment of cancer, autoimmune disease, metabolic disease, and infectious disease. New ways to generate antigen-specific T and B cells inexpensively and with minimal reactogenicity are badly needed. Certain bacterial strains from the gut microbiome elicit a potent, specific adaptive immune response. The underlying mechanisms could guide new therapeutic strategies in which bacteria-specific immune responses are rationally altered or re-directed. The gut is the site of a wide variety of microbe-microbe and microbe-host interactions. However previous papers have characterized microbial strains of the microbiome under artificial conditions of mono-colonization. This approach can identify strains that are capable of modulating immune cells, but it is unknown how a strain functions in the presence of other members of the complex microbiota. This knowledge gap hinders a logical design of a microbial therapeutic. My long-term research objective is to develop new technologies to understand the “physiological” gut ecosystem at the level of molecular mechanisms so that I can identify immune modulatory bacteria from the microbiome and build new therapeutics. In this proposal, I will establish a “physiological” gut by colonizing germ-free mice with a complex defined gut community (104 strains) and profile T cell responses to each strain individually. In Aim1, I will identify a set of bacteria-reactive TCRs and their stimulatory strain by single cell technologies, so that I can provide a big picture of the strain-T-cell interactions at the single TCR level. In Aim2, I will identify and characterize a bacterial antigen common to multiple strains. In Aim3, the result of T cell profiling will be used to “design” therapeutic bacterial communities in which inflammatory strains will be dropped out for building a tolerogenic community to treat colitis in an IBD mouse model. The successful completion of this project will “decode” a strain-by-strain view of immune modulation by the gut microbiome and provide a molecular basis for “designing” the new therapy that logically modulates immune response to treat IBD and other devastating systemic disorders. Support from the K99 and mentors will complement my expertise in immunology with state-of-art technologies in microbiology and single cell biology. I will accomplish this with training from Dr. Michael Fischbach (primary mentor, bacterial genetics), Dr. Daniel Mucida (co-mentor, single-cell biology and T cell biology), Dr. Justin Sonnenburg (advisory committee, metagenomic analysis), and Dr KC Huang, (advisory committee, a synthetic microbial community). The training and mentorship I receive during my K99/R00 award will provide a critical stepping stone for me to achieve my academic goal of establishing a vibrant independent research program that can answer an important question in the gut ecosystem for establishing a new therapeutic.

项目总结/文摘