Dissecting microbiota-driven lymphangiogenesis in immune health and disease

项目摘要 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。 健康和疾病的免疫反应。肠道微生物群与 免疫性疾病的数量，包括癌症、自身免疫、IBD和感染; 然而，具体机制仍不清楚。 我们最近的研究结果表明，肠道微生物群的选择成员驱动淋巴 三级淋巴结构的发育和形成。具体地，添加粘附剂， 结肠驻留细菌，肝螺杆菌，支持淋巴管生成和三级 结直肠肿瘤小鼠结肠内淋巴样结构的形成。最终这 导致T细胞向肿瘤核心的免疫浸润增加。 然而，如何选择结肠细菌驱动淋巴管生成和支持三级淋巴 结构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样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， 肝螺杆菌驱动淋巴管生成和三级淋巴样结构成熟 通过上调VEGF驱动的重编程Lyve 1+巨噬细胞。完成这些 目的将导致一个全新的领域的研究和理解淋巴管生成在 成人主机，也将建立必要的基础，我的职业生涯作为一个独立的 调查员

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.