Microbiota-gamma delta IEL-Paneth cell axis in host antimicrobial response

宿主抗菌反应中的微生物群-γ δ IEL-潘氏细胞轴

• 批准号: 10817443
• 负责人: Karen Leigh Edelblum
• 金额: $ 21.05万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10817443
• 关键词: Affect; American; Anti-Bacterial Agents; Antigens; Behavior; Bilophila; Biological Process; Cell Degranulation; Cell Separation; Cell physiology; Cell secretion; Cells; Chronic; Coculture Techniques; Communicable Diseases; Communication; Crohn' s disease; Data; Development; Disease; Disease remission; Enteral; Enterocytes; Epithelial Cells; Epithelium; Exhibits; Extracellular Space; Family; First Degree Relative; Frequencies; Gene Expression Regulation; Genes; Germ-Free; Goals; Homeostasis; Host Defense; Human; Ileal Diseases; Ileitis; Imaging technology; Immune; Immune System Diseases; Immune system; Immunologic Surveillance; In Vitro; Individual; Inflammatory; Inflammatory Bowel Diseases; Intestines; Knowledge; Lateral; Lymphocyte; Maintenance; Mediating; Microbe; Mission; Modeling; Mucosal Immune System; Mucosal Immunity; Mucous Membrane; Mus; National Institute of Allergy and Infectious Disease; Paneth Cells; Pathology; Patients; Permeability; Phenotype; Population; Production; Proliferating; Public Health; Receptor Cell; Reporter; Research; Role; Signal Transduction; Small Intestines; Speed; T-Cell Receptor; T-Lymphocyte; Therapeutic; United States National Institutes of Health; Up-Regulation; Variant; Villous; Work; antimicrobial; antimicrobial peptide; cell type; commensal bacteria; enteric infection; experimental study; gut inflammation; human disease; immunoregulation; in vivo; insight; intestinal barrier; intestinal epithelium; intestinal homeostasis; intraepithelial; microbial; microbiota; migration; mouse model; new therapeutic target; novel; novel therapeutic intervention; prevent; receptor-mediated signaling; response; transcriptome sequencing

PROJECT SUMMARY. Maintenance of an intact intestinal barrier is critical to prevent microbial activation of mucosal immunity. gd intraepithelial lymphocytes (IEL) migrate extensively within the epithelial compartment to serve as a first line of defense against luminal antigens and invasive enteric microbes, and have been implicating in regulating Paneth cell secretion of antimicrobial peptides. Although microbial-derived molecules contribute to gd IEL homeostasis, specific commensal bacteria have yet to be associated with alterations in gd IEL number and/or function. Moreover, the extent to which gd IEL-mediated signaling influences Paneth cell function has yet to be explored. In preliminary data generated for this application, we identified 5 amplicon sequence variants (ASV) that are strongly associated with the expansion of gd IELs under homeostatic conditions. We also show that epithelial cells isolated from WT mice with an expanded gd IEL compartment also exhibit a significant upregulation of genes involved in Paneth cell antimicrobial peptide production and secretion. Therefore, this proposal seeks to identify the contribution of individual commensals to the expansion of the gd IEL compartment and determine the extent of gd IEL-Paneth cell crosstalk in WT mice exhibiting this hyperproliferative phenotype. Using an integrated approach that combines unique mouse models and cutting edge imaging technologies both in vitro and in vivo, these studies will be the first to identify the contribution of individual commensals in the amplification of gd IEL proliferation and surveillance behavior, and elucidate whether gd IELs directly promote Paneth cell function. Developing a better understanding of the microbiota-gd IEL-Paneth cell axis may identify novel therapeutic targets to aid in host defense and help maintain remission in Crohn’s disease patients.

项目总结。 维持完整的肠道屏障是防止粘膜微生物活化的关键 豁免权。GD上皮内淋巴细胞(IEL)在上皮室内广泛迁移至 作为抵御管腔抗原和入侵肠道微生物的第一道防线，一直是 参与调节潘氏细胞抗菌肽的分泌。尽管微生物来源 分子有助于gdiel的动态平衡，特定的共生细菌尚未联系在一起。 具有GDIEL编号和/或功能的改变。此外，gd IEL在多大程度上 信号对Paneth细胞功能的影响还有待研究。在为此生成的初步数据中 应用，我们确定了5个扩增子序列变体(ASV)，它们与 动态平衡条件下gd iels的扩张。我们还表明，从WT分离的上皮细胞 Gd IEL间隔区扩大的小鼠也表现出显著的基因上调 Paneth细胞抗菌肽的产生和分泌。因此，这项提案试图确定 个体共生体对Gd IEL隔间的扩展的贡献并确定 WT小鼠表现出这种高增殖表型的gd IEL-Paneth细胞串扰的程度。 使用将独特的鼠标模型和尖端图像相结合的集成方法 无论是在体外还是在体内，这些研究都将首次确定 Gd IEL增殖和监测行为扩增的个体共同点 阐明gd IEL是否直接促进Paneth细胞功能。更好地了解 微生物群-gd IEL-Paneth细胞轴可能识别新的治疗靶点，以帮助宿主防御和 帮助克隆氏病患者维持病情缓解。