The Function and Microbial Regulation of Innate Lymphoid Cells in IBD

描述（由申请人提供）：炎症性肠病（IBD）影响超过100万美国人。虽然在许多情况下药物治疗使我们能够控制疾病，但IBD仍然导致显著的发病率和死亡率。一个重要的遗传途径 在IBD中被识别的是由称为白细胞介素（IL）-23的分子激活的。最近，发现了一种新型的淋巴细胞，称为先天淋巴细胞（ILC），对IL-23有反应。本提案的目的是支持我的额外研究培训，以描述该职能的特点， IBD中ILC的调节，并帮助我过渡到一个独立的研究生涯，专注于IBD中免疫细胞的微生物调节。肠道免疫细胞激活的微生物调节专家Dan Littman博士和微生物依赖性肠道炎症专家Timothy Wang博士将担任该提案的共同导师。首先，将使用最先进的测序技术来定义来自从患有IBD（或非IBD）供体的患者的肠分离的ILC的遗传物质（即RNA）。我将参加序列分析的正式培训，以分析这些数据并确定IBD患者肠道ILC中激活的基因/遗传途径。我的建议的第二个主要方面是定义这些肠道ILC与树突状细胞（DC）的相互作用，树突状细胞是一种专门的免疫细胞，可以在炎症部位捕获蛋白质，并将加工后的蛋白质呈递给T细胞以刺激免疫反应。小鼠肠道内存在几种类型的DC，具有不同的捕获蛋白质和/或刺激T细胞的能力。为了研究它们与ILC的相互作用，我将使用我们实验室中产生的新型小鼠模型，使我能够用荧光标记追踪特定的DC亚群，并在活小鼠中消融特定的DC亚群。此外，我将描述DC亚群存在于人类结肠和评估他们的能力，相互作用与人类肠道ILC文化。最后，这项工作将使用“无菌”小鼠来测试来自IBD和非IBD供体的特定细菌支持ILC活性的能力 在结肠炎的小鼠模型中。为了提供科学反馈和职业发展建议，我组建了一个咨询委员会，包括IBD免疫学专家Lloyd Mayer博士;人类免疫学专家Megan Sykes博士;肠道微生物学专家Martin Blaser博士;科学研究职业发展专家Jaime Rubin博士。有了这个科学和职业发展计划，我相信这个建议将为IBD的疾病发病机制以及诊断和治疗策略提供新的见解，并为我过渡到独立的研究生涯奠定坚实的基础。

DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD) affects over 1 million Americans. Although in many circumstances medications have allowed us to gain control of disease, IBD still results in significant morbidity and mortality. One important genetic pathway identified in IBD is activated by a molecule called interleukin(IL)-23. Recently, a new type of lymphocyte, called an innate lymphoid cell (ILC), was discovered that responds to IL-23. The aim of this proposal is to support my additional research training to characterize the function and regulation of ILCs in IBD and help me transition to an independent research career focused on microbial regulation of immune cells in IBD. Dr. Dan Littman, an expert in the microbial regulation of intestinal immune cell activation, and Dr. Timothy Wang, an expert in microbial-dependent intestinal inflammation, will serve as co-mentors of this proposal. First, genetic material (i.e. RNA) from ILCs isolated from the intestines of patients with IBD (or non- IBD) donors will be defined using state-of-the-art sequencing technology. I will participate in formal training in sequence analysis in order to analyze this data and define genes/genetic pathways activated in intestinal ILCs of patients with IBD. The second main aspect of my proposal is to define the interaction of these intestinal ILCs with dendritic cells (DCs), specialized immune cells that capture proteins at sites of inflammation and present the processed protein to T cells to stimulate an immune response. Several types of DCs exist within the mouse intestine with different capacity to capture proteins and/or stimulate T cells. In order to investigate their interaction with ILCs, I will use novel mouse models generated in our lab that allow me to track particular DC subsets with a fluorescent label and to ablate specific DC subsets in a live mouse. Furthermore, I will characterize the DC subsets present in the human colon and evaluate their ability to interact with human intestinal ILCs in culture. Finally, this work will use "germ-free" mice to test the ability of particular bacteria from IBD and non-IBD donors to support ILC activity in mouse models of colitis. In order to provide scientific feedback and career development advice, I have assembled an Advisory Committee including Dr. Lloyd Mayer, an expert in IBD immunology; Dr. Megan Sykes, an expert in human immunology; Dr. Martin Blaser, an expert in intestinal microbiology; and Dr. Jaime Rubin, an expert in scientific research career development. With this scientific and career development plan, I believe this proposal will offer new insight into disease pathogenesis as well as diagnostic and therapeutic strategies for IBD and serve as a strong foundation for my transition to an independent research career.