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

• 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
• 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

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.

项目概要/摘要 免疫调节对于癌症、自身免疫性疾病、代谢性疾病的治疗具有巨大的前景 疾病和传染病的新方法，廉价地产生抗原特异性 T 和 B 细胞。 肠道微生物组中的某些细菌菌株迫切需要最小的反应原性。 特异性适应性免疫反应的潜在机制可以指导新的治疗策略。 哪些细菌特异性免疫反应被合理地改变或重新定向肠道是广泛的部位。 然而，以前的论文已经描述了各种微生物-微生物和微生物-宿主相互作用。 这种方法可以识别人工条件下微生物组的微生物菌株的单一定殖。 能够调节免疫细胞的菌株，但尚不清楚菌株在存在的情况下如何发挥作用 这种知识差距阻碍了微生物的逻辑设计。 治疗性的。 我的长期研究目标是开发新技术来了解“生理”肠道 在分子机制水平上研究生态系统，以便我能够从环境中识别免疫调节细菌 微生物组并建立新的疗法在这个提案中，我将通过殖民建立一个“生理”肠道。 具有复杂的肠道群落（104 种菌株）的无菌小鼠，并分析 T 细胞对每种菌株的反应 在 Aim1 中，我将通过单细胞识别一组细菌反应性 TCR 及其刺激菌株。 技术，这样我就可以在单个 TCR 水平上提供菌株与 T 细胞相互作用的全景图。 Aim2，我将鉴定并表征多种菌株共有的细菌抗原。Aim3，T 细胞的结果。 分析将用于“设计”治疗性细菌群落，其中炎症菌株将被 因在 IBD 小鼠模型中建立耐受性群落来治疗结肠炎而退出。 该项目的完成将“解码”肠道微生物组免疫调节的逐株视图 并为“设计”新疗法提供分子基础，逻辑上调节免疫反应 治疗 IBD 和其他破坏性系统性疾病。 K99 和导师的支持将用最先进的技术补充我在免疫学方面的专业知识 我将通过迈克尔博士的培训来完成微生物学和单细胞生物学技术。 Fischbach（主要导师，细菌遗传学）、Daniel Mucida 博士（共同导师，单细胞生物学和 T 细胞） 生物学）、Justin Sonnenburg 博士（宏基因组分析顾问委员会）和 KC Huang 博士（顾问委员会） 我在获得 K99/R00 奖期间接受的培训和指导。 将为我实现建立充满活力的独立性的学术目标提供关键的垫脚石 研究计划可以回答肠道生态系统中的一个重要问题，从而建立一个新的 治疗性的。