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.

项目总结 高度专门化的肠道免疫系统负责维持对来自 食物和共生菌，同时提供对病原体的保护性免疫。对这一点的失调 临界平衡可导致食物过敏、炎症性肠病(IBD)或增加对肠道的易感性 病原体。树突状细胞(DC)是肠道内环境稳定的关键分子，它能很好地协调免疫 呈递管腔抗原和诱导CD4+T细胞功能分化为调节性T细胞的反应 或促炎性亚群。在耐受或免疫之间做出决定的细胞机制 对肠道抗原的作用仍不清楚，很大程度上是因为确切的DC的鉴定和特征 参与这些过程是一个长达数十年的技术挑战。为了克服这个问题，我 建立了LIPSTIC(通过分类标记细胞间接触来标记免疫伙伴关系)的使用 肠道中的技术，这使得特定的肠道细胞-细胞相互作用的标记能够依赖于接近。这个 这项研究提案的主要目的是阐明决定DC是否会诱导 体内调节性或促炎性T细胞，通过结合LIPSTIC系统和基因打靶，功能 成像、跨部门遗传学和基于相互作用的转录组学方法。这项提案考验着 假设肠道中存在专用于不同功能的DC，并且持续动态 根据管腔含量对DC亚群的重新编程决定了对食物和微生物的耐受性或免疫力。 具体地说，这一概念将在生理(对食物和微生物的耐受性)和 病理情况(过敏、肠道感染和结肠炎)。为此，K99指导阶段 (目标1)将揭示引起对食物和细胞的耐受或炎症的DC的确切性质 食物特异性pTregs维持口服耐受的分子机制。接下来，R00独立阶段 (目标2)将重点研究对共生的免疫反应，与结肠炎等疾病的相关性。 阐明DC群体、定位和分子机制与不同微生物的耐受性 将揭示宿主-微生物在健康和疾病中相互作用的本质。总而言之，这项研究计划将 有助于从根本上洞察某些肠道疾病的病因，并将为 食物过敏、结肠炎和肠道感染的新疗法的开发，对公众具有深远的影响 健康。拟议的发展计划补充了我在粘膜免疫学和细胞方面的培训 与转录组分析、成像和小鼠遗传学的相互作用。我会利用广泛的 洛克菲勒大学的资源、丹尼尔·穆奇达博士、加布里埃尔·维克托拉博士的指导和咨询 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。在结束时， 在辅导阶段，我将配备必要的工具，在交叉口进行全面的学习 作为一名独立的研究人员，研究细胞通讯和免疫反应对共生体的影响。