Human Innate Lymphoid Cells and Regulation of Tissue Homeostasis

人类先天淋巴细胞和组织稳态的调节

基本信息

批准号：
8703316
负责人：
David Artis
金额：
$ 64.85万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8703316
关键词：
3-Dimensional Address Adult Amphiregulin Antibodies B-Lymphocytes Biological Assay Blood Bone Marrow Cell Differentiation process Cell surface Cells Characteristics Chemicals Chronic Collaborations Communities Complement Data Dendritic Cells Development Disease Environment Epidermal Growth Factor Receptor Epithelial Epithelial Cell Proliferation Epithelial Cells Exhibits Flow Cytometry Growth Factor Heterogeneity Homeostasis Human IL2RA gene IL7R gene Immune Immune response Immune system Immunity Individual Inflammation Inflammatory Injury Instruction Interferon Type II Interleukin-13 Interleukin-17 Interleukin-5 Interleukin-9 Intestines Lung Lymphocyte Lymphoid Lymphoid Cell Lymphoid Tissue Mediating Mus Natural Killer Cells Organ Donor Organoids Outcome Study Pathway interactions Pattern Phenotype Population Population Group Public Health Regulation Relative (related person)Resistance STAT3 gene STAT6 gene Signal Transduction Site Skin Spleen Surface System T-Lymphocyte Testing Therapeutic Tissue Sample Tissues Wound Healing base body map cytokine design enteric pathogen genome-wide genome-wide analysis granulocyte human disease human tissue inhibitor/antagonist insight interleukin-22 lymph nodes macrophage microbial mucosal site new therapeutic target novel novel therapeutics novel vaccines programs repaired response tissue repair transcription factor

项目摘要

Chronic infectious and inflammatory diseases of humans are a significant public health challenge worldwide and greater understanding the human immune system will be essential in the design of new therapies to target these conditions. While significant advances have been made in defining the development and function of the murine immune system, a lack of access to non-diseased human tissue samples has hampered our progress in defining the phenotype and functional potential of immune cells isolated from different human tissue sites. Elucidating a whole body map ofthe human immune system will provide fundamental new insights into the pathways that regulate immunity and chronic inflammation that could aid in the design of new vaccines and immuno-therapeutic approaches. The focus of this proposal is to test whether human lymphoid versus non-lymphoid tissues are populated with phenotypically and functionally distinct innate lymphoid cells (ILCs) and to interrogate the functional significance of ILCs in maintaining tissue homeostasis in the lung and intestine. Employing flow cytometry and genome-wide transcriptional profiling, studies outlined in Aim 1 will comprehensively characterize the phenotypic and functional potential of tissue-resident ILCs isolated from the bone marrow, blood, spleen, lymph nodes, lung and intestine. To complement this analysis, we will also test whether ILCs isolated from distinct tissue sites exhibit differential responsiveness to host-derived cytokines versus microbial products. Using a novel ex vivo 3-dimensional human organoid culture system, studies in Aim 2 will test how ILCs isolated from lymphoid versus lung and intestinal barrier sites can differentially regulate epithelial cell proliferation, differentiation, barrier function and repair. Using antibody-mediated blockade approaches and chemical inhibitors, we will also test the differential contribution of different cytokine-dependent pathways in ILC-mediated regulation of epithelial function in both the lung and intestine organoid systems.

人类慢性传染病和炎症性疾病是全球面临的重大公共卫生挑战更好地了解人类免疫系统对于设计新疗法至关重要瞄准这些条件。虽然在定义发展和由于无法获得未患病的人体组织样本，小鼠免疫系统的功能受到影响阻碍了我们在定义从分离的免疫细胞的表型和功能潜力方面取得的进展不同的人体组织部位。阐明人体免疫系统的全身图谱将提供对调节免疫和慢性炎症途径的基本新见解可能有助于新疫苗和免疫治疗方法的设计。该提案的重点是测试人类淋巴组织与非淋巴组织是否具有表型和功能不同的先天淋巴细胞 (ILC) 并探讨 ILC 在维持肺和肠的组织稳态。采用流式细胞术和全基因组转录分析，目标 1 中概述的研究将全面表征表型和功能潜力从骨髓、血液、脾脏、淋巴结、肺和肠中分离出的组织驻留 ILC。到为了补充这一分析，我们还将测试从不同组织部位分离的 ILC 是否表现出差异对宿主衍生细胞因子与微生物产物的反应。使用新颖的离体 3 维人类类器官培养系统，目标 2 中的研究将测试如何从淋巴和肺中分离 ILC 肠屏障位点可以差异调节上皮细胞增殖、分化、屏障功能和维修。使用抗体介导的阻断方法和化学抑制剂，我们还将测试不同细胞因子依赖性途径在ILC介导的上皮细胞调节中的不同贡献在肺和肠类器官系统中发挥功能。