Epithelial antigen presentation in regulation of the host-microbiota relationship

上皮抗原呈递在调节宿主-微生物群关系中的作用

• 批准号: 10374870
• 负责人: Emily M. Eshleman
• 金额: $ 7.17万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10374870
• 关键词: Address; Animals; Antigen Presentation; Antigen-Presenting Cells; Antigens; Bacteria; Bacterial Antigens; CD4 Positive T Lymphocytes; Cells; Chronic; Coculture Techniques; Colitis; Data; Dendritic Cells; Development; Disease; Disease model; Environment; Epithelial; Epithelial Cells; Equilibrium; Exhibits; Exposure to; Foundations; Gastrointestinal tract structure; Germ-Free; Goals; Gut associated lymphoid tissue; Homeostasis; Immune; Immune response; Immune system; Immunity; Immunology; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestinal Diseases; Intestines; Knockout Mice; Knowledge; Link; Location; Lymphocyte Activation; Major Histocompatibility Complex; Mediating; Mentors; Mentorship; Microbe; Microbiology; Modeling; Modernization; Mucosal Immunity; Mucous Membrane; Mus; Mutant Strains Mice; Natural Immunity; Organoids; Pathogenicity; Pediatric Hospitals; Play; Process; Reagent; Regulation; Research; Research Personnel; Role; T cell response; T-Cell Activation; T-Lymphocyte; Techniques; Testing; Training; Transgenic Mice; Work; beneficial microorganism; career; commensal bacteria; commensal microbes; experience; gut inflammation; gut microbiota; host microbiota; human disease; immune activation; immunoreaction; immunoregulation; in vivo; innovation; insight; interest; intestinal barrier; intestinal epithelium; intestinal homeostasis; macrophage; microbial colonization; microbiota; mouse model; neonatal mice; novel; novel strategies; pathogen; pathogenic bacteria; prevent; response; tool; uptake

Project Summary Despite a clear link between intestinal immunity and the microbiota, the mechanisms regulating host immune responses to commensal microbes remain poorly understood. Intestinal epithelial cells (IECs) reside at the direct interface between the microbiota and dynamic immune cells and are thus uniquely poised to calibrate host immunity. Although IECs are likely critical for deciphering harmful versus harmless antigens and instructing the appropriate immune reaction, remarkably little is known about mechanisms that enable IECs to modulate host- microbiota interactions. Antigen presenting cells (APCs) must differentiate between harmless and harmful antigens and coordinate proper T cell responses. Although atypical APCs, my preliminary data demonstrate that IECs are the most abundant MHCII-expressing cells in the intestine and that MHCII expression in IECs is directly upregulated by microbiota. Thus, I hypothesize that epithelial antigen presentation may be essential for mediating host-microbiota interactions that impact intestinal homeostasis and inflammation. Studies outlined in this proposal will directly test this hypothesis by defining the function of IEC-intrinsic MHCII. Employing newly developed mutant mouse strains, intestinal organoids, and established models of intestinal inflammation, two specific aims are proposed that will determine (i) the influence of IEC-intrinsic MHCII expression on mucosal barrier function and immune homeostasis and (ii) how IEC-intrinsic MHCII regulates development of intestinal inflammation. Collectively, these studies will provide new insights into how microbiota direct intestinal immunity and will guide novel approaches for investigating and treating intestinal inflammatory diseases. During my past research experiences, I discovered my strong interest in the host-microbiota relationship. For this reason, I initiated the proposed project with Dr. Theresa Alenghat that will build upon my knowledge of innate immunity and antigen presentation and enable me to transition into the field of mucosal immunology. My thesis work provided me with an excellent foundation in host-pathogen interactions, microbiology, and immunology, but I have not had previous exposure to epithelial regulation, antigen-specific techniques, and intestinal disease models. The labs of my mentors, Dr. Alenghat and Dr. Sing Sing Way, along with the exceptional scientific and intellectual environment at Cincinnati Children’s Hospital will enable me to utilize modern, innovative approaches in my research and collaborate with top investigators. Over the next three years, I fully anticipate that my background in conjunction with my current training plan will allow me to successfully carry out the proposed project. The mentoring and training I will receive will enable me to successfully transition to an independent research career that can address questions directed towards fundamental advances in mucosal immunity, as well as innovative and targeted strategies for investigating microbiota-sensitive diseases.

项目摘要 尽管肠道免疫与微生物群之间有明确的联系，但调节宿主免疫的机制 对共生微生物的反应仍然很了解。肠上皮细胞（IEC）位于直接 微生物群和动态免疫细胞之间的接口，因此被校准宿主唯一中毒 免疫。尽管IEC可能对破译有害抗原与无害抗原和指导 适当的免疫反应，关于使IEC能够调节宿主的机制知之甚少。 微生物群相互作用。抗原呈递细胞（APC）必须区分无害和有害 抗原和协调适当的T细胞反应。尽管非典型APC，但我的初步数据表明 IEC是肠中最丰富的MHCII表达细胞，IEC中的MHCII表达直接 由微生物群上调。那我假设上皮抗原表现可能对 介导会影响肠道稳态和炎症的宿主菌相互作用。概述的研究 该建议将通过定义IEC Intrinsic MHCII的功能直接检验该假设。新雇用 开发了突变的小鼠菌株，肠癌和已建立的肠道注射模型，两个 提出了具体目的，该目标将确定（i）IEC Intrinsic MHCII对粘膜的影响 障碍功能和免疫稳态以及（ii）IEC Intrinsic MHCII如何调节肠道的发展 炎。总的来说，这些研究将为微生物群如何直接肠道免疫提供新的见解 并将指导新的方法来研究和治疗肠道炎症性疾病。 在过去的研究经历中，我发现了对宿主 - 微生物关系的强烈兴趣。 因此，我与Theresa Alenghat博士一起启动了拟议的项目，该项目将基于我对 先天免疫学和抗原表现，使我能够过渡到粘膜免疫学领域。我的 论文的工作为我为宿主 - 病原体相互作用，微生物学和 免疫学，但我以前没有接触过上皮调节，抗原特异性技术和 肠道疾病模型。我的导师的实验室Alenghat博士和Sing Sing Way博士以及 辛辛那提儿童医院的卓越科学和智力环境将使我能够利用 在我的研究中，现代，创新的方法与顶级研究人员合作。在接下来的三年中， 我完全期望我的背景与当前的培训计划结合在一起，将使我成功 执行拟议的项目。我将收到的心理和培训将使我成功过渡 进入独立的研究职业，可以解决针对基本进展的问题 粘膜免疫，以及研究微生物群敏感性疾病的创新和有针对性的策略。