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.

项目总结/摘要 免疫调节在癌症、自身免疫性疾病、代谢性疾病、免疫性疾病和免疫性疾病的治疗中具有巨大的前景。 疾病和传染病。廉价地产生抗原特异性T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引发了一种有效的， 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， 这些细菌特异性免疫应答被合理地改变或重新定向。肠道是一个广泛的 微生物-微生物和微生物-宿主相互作用的多样性。然而，以前的论文已经描述了 微生物组的微生物菌株在人工条件下的单定殖。这种方法可以识别 能够调节免疫细胞的菌株，但尚不清楚菌株如何在存在免疫细胞的情况下发挥作用。 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， 有治疗作用的 我的长期研究目标是开发新技术来了解“生理”肠道 在分子机制的水平上研究生态系统，这样我就可以从 微生物组和建立新的疗法。在这个建议中，我将建立一个“生理”肠道， 无菌小鼠，具有复杂的确定的肠道群落（104株），并描述T细胞对每种菌株的应答 单独地在Aim 1中，我将通过单细胞培养鉴定一组细菌反应性TCR及其刺激株， 技术，这样我就可以在单个TCR水平上提供一个菌株-T细胞相互作用的大图。在 目标2，我将鉴定和表征多种菌株共有的细菌抗原。在Aim 3中，T细胞的结果 分析将用于“设计”治疗性细菌群落，其中炎性菌株将被 因为在IBD小鼠模型中建立耐受原性社区来治疗结肠炎而退出。成功 该项目的完成将“解码”肠道微生物组对免疫调节的逐株视图 并为“设计”新疗法提供分子基础， 治疗IBD和其他破坏性的系统性疾病。 来自K99和导师的支持将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完成这一目标 Fischbach（主要导师，细菌遗传学）、丹尼尔·穆西达博士（共同导师，单细胞生物学和T细胞 Justin Sonnenburg博士（咨询委员会，宏基因组分析）和KC Huang博士（咨询委员会， 一个合成的微生物群落）。我在获得K99/R 00奖项期间接受的培训和指导 将提供一个关键的垫脚石，我实现我的学术目标，建立一个充满活力的独立 研究计划，可以回答一个重要的问题，在肠道生态系统建立一个新的 有治疗作用的