Dissecting microbiota-driven lymphangiogenesis in immune health and disease

剖析免疫健康和疾病中微生物驱动的淋巴管生成

基本信息

批准号：
10722819
负责人：
Abigail E Overacre-Delgoffe
金额：
$ 46.72万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10722819
关键词：
Address Adult Autoimmunity Automobile Driving B-Lymphocytes Bacteria Cells Chronic Colitis Collaborations Colon Colorectal Neoplasms Communities Development Disease Ensure Environment Follicular Dendritic Cells Foundations Gastrointestinal tract structure Goals Growth Health Helicobacter hepaticus Helper-Inducer T-Lymphocyte Homeostasis Human ITGAM gene Immune Immune System Diseases Immune response Immunologics Immunology Infection Inflammation Inflammatory Knowledge Lymphangiogenesis Lymphatic Lymphatic Endothelial Cells Lymphoid Tissue Macrophage Malignant Neoplasms Mediating Microbe Mucous Membrane Mus Patients Polysaccharides Production Regulation Research Research Personnel Resources Role Severity of illness Signal Transduction Structure Structure of germinal center of lymph node System T cell infiltration T-Lymphocyte Testing Tumor Immunity Universities Up-Regulation Vascular Endothelial Growth Factors Virus Work career colon bacteria dysbiosis field study fungus gut microbes gut microbiota high reward high risk host microbiota immune activation immune cell infiltrate immune health immunogenic in vivo lymphatic development lymphatic vessel member microbiome microbiota mouse model novel patient prognosis post-doctoral training programs response spatiotemporal success tertiary lymphoid organ transcriptomics tumor

项目摘要

Project Summary The goal of this proposal is to investigate the role of the gut microbiota and microbiota-specific immune responses in health and disease. The gut microbiota has been associated with a number of immune-based diseases, including cancer, autoimmunity, IBD and infections; however, specific mechanisms remain unclear. Our recent findings have shown that select members of the gut microbiota drive lymphatic development and formation of tertiary lymphoid structures. Specifically, addition of an adherent colonic-residing bacteria, Helicobacter hepaticus, supports lymphangiogenesis and tertiary lymphoid structure formation within the colon of colorectal tumor-bearing mice. Ultimately, this led to an increase in immune infiltration by T cells into the tumor core. However, how select colonic bacteria drive lymphangiogenesis and support tertiary lymphoid structure formation and maturation remains unknown. Project 1 of this proposal will identify the key signals responsible for bacteria-drive lymphangiogenesis using spatio-temporal analysis. Part 2 will investigate the cell subsets responsible for tertiary lymphoid structure formation due to lymphangiogenesis and Part 3 will assess the direct and indirect roles of gut microbes in lymphangiogenesis in health and disease. Our overall hypothesis is that colonization with Helicobacter hepaticus drives lymphangiogenesis and tertiary lymphoid structure maturation through upregulation of VEGF-driven reprogrammed Lyve1+ macrophages. Completion of these aims will lead to a completely new field of study and understanding of lymphangiogenesis in the adult host and will also establish the necessary foundation for my career as an independent investigator.

项目概要该提案的目标是研究肠道微生物群和微生物群特异性的作用健康和疾病中的免疫反应。肠道微生物群与以下因素有关：许多基于免疫的疾病，包括癌症、自身免疫、炎症性肠病和感染；然而，具体机制仍不清楚。我们最近的研究结果表明，肠道微生物群的特定成员驱动淋巴三级淋巴结构的发育和形成。具体来说，添加粘附剂结肠驻留细菌，肝螺杆菌，支持淋巴管生成和第三级血管生成结直肠肿瘤小鼠结肠内淋巴结构的形成。最终，这导致 T 细胞对肿瘤核心的免疫浸润增加。然而，选择结肠细菌如何驱动淋巴管生成并支持三级淋巴结构的形成和成熟仍然未知。本提案的项目 1 将确定使用时空分析负责细菌驱动淋巴管生成的关键信号。第 2 部分将研究负责三级淋巴结构形成的细胞亚群第 3 部分将评估肠道微生物在淋巴管生成中的直接和间接作用健康和疾病中的淋巴管生成。我们的总体假设是殖民化肝螺杆菌驱动淋巴管生成和三级淋巴结构成熟通过上调 VEGF 驱动的重编程 Lyve1+ 巨噬细胞。完成这些目标将导致对淋巴管生成的全新研究和理解领域成人主持人，也将为我的独立职业生涯奠定必要的基础研究者。