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。廉价且高效地生成抗原特异性 T 细胞和 B 细胞的新方法 迫切需要最小的反应原性。来自肠道微生物组的某些​​细菌菌株会产生有效的、 特异性适应性免疫反应。潜在的机制可以指导新的治疗策略 哪些细菌特异性的免疫反应被合理地改变或重新定向。肠道是广泛的部位 各种微生物与微生物以及微生物与宿主的相互作用。然而之前的论文已经描述了 在人工单一定殖条件下微生物组的微生物菌株。这种方法可以识别 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 复杂微生物群的其他成员。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 单独。在Aim1中，我将通过单细胞鉴定一组细菌反应性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 细胞相互作用的全貌。在 目标2，我将识别并表征多种菌株共有的细菌抗原。 Aim3中，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。成功者 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 微生物学和单细胞生物学技术。我将通过迈克尔博士的培训来实现这一目标 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） 委员会，一个合成微生物群落）。我在 K99/R00 获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。