The Function and Microbial Regulation of Innate Lymphoid Cells in IBD

IBD 中先天淋巴细胞的功能和微生物调节

• 批准号: 8910696
• 负责人: randy s longman
• 金额: $ 15.35万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8910696
• 关键词: Ablation; Activities of Daily Living; Advisory Committees; Affect; American; Bacteria; CX3CL1 gene; Cell physiology; Cells; Chemicals; Clinical; Coculture Techniques; Colitis; Colon; Critical Pathways; Crohn' s disease; Data; Data Analyses; Dendritic Cells; Development; Development Plans; Diagnostic; Disease; Endoscopic Biopsy; Epithelial Cells; Escherichia coli; Excision; Feedback; Foundations; Genes; Genetic; Genetic Materials; Germ-Free; Gnotobiotic; Healed; Health; Homeostasis; Human; IL7R gene; Immune; Immune Cell Activation; Immune response; Immunology; In Situ; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Intestines; Label; Laboratories; Life; Ligands; Link; Lymphocyte; Lymphoid Cell; Mentors; Metabolic; Microbe; Microbiology; Microscopy; Modeling; Morbidity - disease rate; Mus; Operative Surgical Procedures; Orphan; PTPRC gene; Pathogenesis; Pathway interactions; Patients; Pattern recognition receptor; Pharmaceutical Preparations; Phenotype; Play; Population; Predisposition; Process; Production; Proteins; Proto-Oncogene Protein c-kit; RNA; Recombinant DNA; Regulation; Research; Research Training; Role; Sequence Analysis; Signal Pathway; Signal Transduction; Site; Sorting - Cell Movement; Stream; Surface; System; T-Lymphocyte; Technology; Testing; Therapeutic; Tissues; Training; Transcriptional Regulation; Tretinoin; Work; base; career; career development; disorder control; gut microbiota; healing; in vivo; inhibitor/antagonist; insight; interleukin-22; interleukin-23; metagenome; metagenomic sequencing; microbial; mortality; mouse model; novel; novel diagnostics; novel therapeutics; receptor; response; small hairpin RNA; transcription factor; transcriptome sequencing

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.

描述（由申请人提供）：炎症性肠病 (IBD) 影响超过 100 万美国人。尽管在许多情况下药物可以让我们控制疾病，但 IBD 仍然会导致显着的发病率和死亡率。一条重要的遗传途径 IBD 中发现的这种物质是由一种称为白细胞介素 (IL)-23 的分子激活的。最近，发现了一种新型淋巴细胞，称为先天淋巴细胞 (ILC)，它对 IL-23 做出反应。该提案的目的是支持我额外的研究培训，以描述功能和 ILC 在 IBD 中的调节，帮助我过渡到专注于 IBD 中免疫细胞的微生物调节的独立研究生涯。肠道免疫细胞激活微生物调节专家 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从 IBD 患者（或非 IBD）供体肠道中分离的 ILC 的遗传物质（即 RNA）。我将参加序列分析的正式培训，以便分析这些数据并定义 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，可以捕获炎症部位的蛋白质并将加工后的蛋白质呈现给 T 细胞以刺激免疫反应。小鼠肠道内存在多种类型的 DC，它们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生成的新型小鼠模型，该模型使我能够用荧光标记跟踪特定的 DC 子集，并消除活体小鼠中的特定 DC 子集。此外，我将描述人类结肠中存在的 DC 亚群的特征，并评估它们与培养物中的人类肠道 ILC 相互作用的能力。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 在小鼠结肠炎模型中。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，其中包括 IBD 免疫学专家 Lloyd Mayer 博士； Megan Sykes博士，人类免疫学专家； Martin Blaser博士，肠道微生物学专家；以及科研职业发展专家 Jaime Rubin 博士。通过这个科学和职业发展计划，我相信该提案将为疾病发病机制以及 IBD 的诊断和治疗策略提供新的见解，并为我过渡到独立研究职业奠定坚实的基础。