Cell-cell interactions driving gut inflammation and tolerance

细胞间相互作用驱动肠道炎症和耐受性

• 批准号: 10739963
• 负责人: Maria Cecilia Campos Canesso
• 金额: $ 13.97万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739963
• 关键词: Address; Advisory Committees; Allergic; Anti-Inflammatory Agents; Antigen-Presenting Cells; Antigens; Automobile Driving; Award; CD4 Positive T Lymphocytes; Cell Communication; Cells; Charge; Colitis; Color; Communication; Complement; Dendritic Cells; Development; Development Plans; Dietary Proteins; Digestive System Disorders; Disease; Equilibrium; Etiology; Face; Flow Cytometry; Food; Food Hypersensitivity; Foundations; Functional Imaging; Gene Targeting; Generations; Genes; Genetic; Goals; Health; Homeostasis; Hypersensitivity; Image; Immune; Immune response; Immune system; Immunity; Immunology; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intestinal Diseases; Intestines; Label; Location; Mentors; Mentorship; Microbe; Molecular; Mucosal Immune Responses; Mucous Membrane; Mus; Nature; Nutrient; Outcome; Pathologic; Pathway interactions; Phase; Physiological; Population; Predisposition; Process; Property; Public Health; Reaction; Regulatory T-Lymphocyte; Research; Research Personnel; Research Proposals; Resources; Role; Stimulus; System; T cell differentiation; T-Cell Activation; T-Lymphocyte; Technology; Testing; Training; Universities; Work; career development; commensal bacteria; confocal imaging; dietary; draining lymph node; effector T cell; enteric infection; enteric pathogen; functional outcomes; gut inflammation; gut microbiota; host-microbe interactions; ileum; imaging genetics; in vivo; insight; intestinal barrier; intestinal homeostasis; microbiome; microbiota; microorganism antigen; migration; mouse genetics; new technology; new therapeutic target; novel; novel therapeutics; oral tolerance; pathogen; preservation; prevent; programs; rational design; response; single-cell RNA sequencing; tool; transcriptomics

Project summary The highly specialized intestinal immune system is charged with maintaining tolerance to harmless stimuli from food and commensal bacteria, while providing protective immunity against pathogens. Dysregulation of this critical balance can lead to food allergy, inflammatory bowel disease (IBD), or increased susceptibility to enteric pathogens. Dendritic cells (DCs) are key players in intestinal homeostasis, finely orchestrating immune responses by presenting luminal antigens and inducing functional differentiation of CD4+ T cells into regulatory or pro-inflammatory subsets. The cellular mechanisms underlying the decision between tolerance or immunity to intestinal antigens remain unknown, largely because the identification and characterization of the exact DCs involved in these processes has been a decades-long technical challenge. To overcome this problem, I established the use of the LIPSTIC (Labeling Immune Partnerships by SorTagging Intercellular Contacts) technology in the gut, which enables proximity-dependent labeling of specific intestinal cell-cell interactions. The main goal of this research proposal is to elucidate the mechanisms that determine whether DCs will induce regulatory or pro-inflammatory T cells in vivo, by combining the LIPSTIC system with gene targeting, functional imaging, intersectional genetics, and interaction-based transcriptomics approaches. This proposal tests the hypothesis that DCs specialized for different functions exist in the intestine and that continuous dynamic reprogramming of DCs subsets by luminal content dictate tolerance or immunity to food and microbes. Specifically, this concept will be tested in mice under physiological (tolerance to food and microbes) and pathological (allergic sensitization, enteric infection, and colitis) scenarios. To this end, the K99 mentored phase (Aim 1) will reveal the exact nature of the DCs that induce tolerance or inflammation to food and the cellular and molecular mechanisms by which food-specific pTregs maintain oral tolerance. Next, the R00 independent phase (Aim 2) will focus on studying immune responses to commensals, with relevance to disorders such as colitis. Elucidating the DC populations, location and molecular mechanisms involved in tolerance to distinct microbes will reveal the nature of host-microbe interactions in health and disease. Together, this research program will lend fundamental insight into the etiology of certain intestinal disorders and will provide foundation for the development of new therapies for food allergy, colitis, and enteric infections, with profound implications for public health. The proposed development plan complements my training in mucosal immunology and cellular interactions with transcriptomics analysis, imaging, and mouse genetics. I will take advantage of the extensive resources of the Rockefeller University, the mentorship of Dr. Daniel Mucida, Dr. Gabriel Victora and the Advisory Committee team that will lend expertise in key aspects of the project and career development. At the end of the mentored phase, I will be equipped with the necessary tools to conduct comprehensive studies at the intersection of cellular communication and immune response to commensals as an independent investigator.

项目摘要 高度专业的肠道免疫系统负责维持对无害刺激的耐受性 食物和共生细菌，同时为病原体提供保护性免疫。失调 临界平衡可以导致食物过敏，炎症性肠病（IBD）或对肠的易感性提高 病原体。树突状细胞（DC）是肠内稳态的关键参与者，精心策划免疫 通过呈现腔抗原和诱导CD4+ T细胞的功能分化的反应 或促炎性子集。耐受性或免疫力之间决策的基础机制 肠道抗原仍然未知，主要是因为确切DC的识别和表征 参与这些过程是长达数十年的技术挑战。为了克服这个问题，我 建立了使用肥大的使用（通过排序细胞间触点来标记免疫伙伴关系） 肠道中的技术，可实现特定肠细胞相互作用的近端依赖性标记。这 该研究建议的主要目标是阐明确定DC是否诱导的机制 通过将肥大系统与基因靶向，功能性相结合，在体内调节或促炎性T细胞 成像，交叉遗传学和基于相互作用的转录组学方法。该建议测试 肠道中存在专门用于不同功能的DC的假设，并且连续动态 通过腔内含量重新编程DCS子集决定了对食物和微生物的耐受性或免疫力。 具体而言，该概念将在小鼠的生理学（对食物和微生物的耐受性）和 病理（过敏敏化，肠道感染和结肠炎）情景。为此，K99指导了阶段 （AIM 1）将揭示DC的确切性质，这些DC会诱导食物和细胞的耐受性或炎症 食物特异性PTREG维持口服耐受性的分子机制。接下来，R00独立阶段 （AIM 2）将专注于研究对共生的免疫反应，与结肠炎等疾病有关。 阐明涉及对不同微生物的耐受性的直流种群，位置和分子机制 将揭示健康和疾病中宿主微生物相互作用的性质。该研究计划将在一起 对某些肠道疾病的病因有根本的洞察力，并将为 开发用于食物过敏，结肠炎和肠道感染的新疗法，对公众产生了深远的影响 健康。拟议的开发计划补充了我在粘膜免疫学和细胞方面的培训 与转录组学分析，成像和小鼠遗传学的相互作用。我将利用广泛的优势 洛克菲勒大学的资源，Daniel Mucida博士的指导，Gabriel Victora博士和咨询 委员会团队将在项目和职业发展的关键方面提供专业知识。在 指导阶段，我将配备在十字路口进行全面研究的必要工具 作为独立研究者的细胞通信和对共生的免疫反应。