Microbiota regulation of intestinal eosinophils

微生物群对肠道嗜酸性粒细胞的调节

基本信息

批准号：
10302260
负责人：
Yiyun Grace Cao
金额：
$ 1.88万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10302260
关键词：
Address Affect Agonist Allergens Allergic Antibiotic Therapy Antigen Targeting Antigens Biological Assay Biology Bromodeoxyuridine Cells Complement Complex Data Dendritic Cells Dendritic cell activation Development Disease Emergency department visit Environment Environmental Risk Factor Eosinophilic Esophagitis Epinephrine Equilibrium FFAR2 gene Fellowship Flow Cytometry Food Food Hypersensitivity Germ-Free Gnotobiotic Granulocyte-Macrophage Colony-Stimulating Factor Homeostasis Human Immune Immunity Immunoglobulin A Immunologics Immunology In Vitro Incidence Inflammation Inflammatory Inflammatory Response Interleukin-5 Intestines Lactobacillus Lead Longevity Measures Mediating Microbe Modeling Mucous Membrane Mucous body substance Mus Pathway interactions Peroxidases Phenotype Play Population Positioning Attribute Predisposition Prevalence Production Regulation Regulatory T-Lymphocyte Research Resistance Role Shapes Signal Transduction Stimulus Th1 Cells Training Work allergic response career cell type collaborative environment cytokine desensitization dietary approach eosinophil experimental study food allergen food antigen germ free condition high salt diet immune activation improved in vivo innovation microbial microbiota new therapeutic target novel therapeutics oral immunotherapy prevent receptor recruit response sensor standard of care success

项目摘要

Abstract Food allergy is characterized by aberrant immune activation in response to an innocuous food antigen and affects 5-8% of the US population. The current standard of care remains limited to allergen avoidance, demonstrating the need for new therapeutic avenues. One promising approach would be to control the initiation of the allergic inflammatory response mediated by T helper 2 (Th2) cells. In food allergy, Th2 cells are induced by antigen- presenting dendritic cells (DCs) in the gut, which in turn are activated by intestinal eosinophils, an innate immune cell type associated with type 2 immunity. Therefore, regulation of intestinal eosinophils represents a promising point at which to intervene at the beginning of an allergic response. Although the gut contains the largest eosinophil population in the body, understanding of the signals controlling their accumulation and function remains limited. An environmental signal likely to regulate intestinal eosinophils is the microbiota, which is critical in shaping intestinal immune cells. Interestingly, microbiota disruption either in germ-free (GF) mice or with antibiotic treatment in both mice and humans is also associated with exacerbation and increased incidence of food allergy, but the mechanism is not entirely clear. I hypothesize that the microbiota regulates intestinal eosinophils and their function in food allergy. My proposed mechanistic studies of intestinal eosinophil regulation by the microbiota will culminate in a peanut antigen food allergy model to determine how this environmental factor controls eosinophil function in disease. Elucidating how gut-specific signals influence eosinophils would improve understanding of their biology and identify novel therapeutic targets for these cells in food allergy. Additionally, the Training Plan developed alongside this Research Plan will provide a blueprint to prepare me for a successful academic career. With the support of my Sponsor and Co-Sponsor in the innovative and collaborative environment at Harvard, this fellowship will enable me to be well poised for an eventual independent position in mucosal immunology.

抽象的食物过敏的特征是对无害食物抗原的异常免疫激活，并影响美国人口的5-8％。当前的护理标准仍然仅限于避免过敏原，证明需要新的治疗途径。一种有前途的方法是控制过敏性的启动 T辅助2（Th2）细胞介导的炎症反应。在食物过敏中，Th2细胞是由抗原诱导的在肠道中呈现树突状细胞（DC），而肠道被肠道嗜酸性粒细胞激活，一种先天的免疫与2型免疫相关的细胞类型。因此，肠道嗜酸性粒细胞的调节代表了有希望的在过敏反应开始时进行干预的点。虽然肠道最大体内嗜酸性粒细胞种群，了解控制其积累和功能的信号仍然有限。可能调节肠道嗜酸性粒细胞的环境信号是菌群，这很关键在塑造肠道免疫细胞中。有趣的是，在无菌（GF）小鼠中或与小鼠和人类的抗生素治疗也与加重和增加的发生率有关食物过敏，但机制并不完全清楚。我假设微生物群调节肠道嗜酸性粒细胞及其在食物过敏中的功能。我提出的对肠道嗜酸性粒细胞调节的机械研究由微生物群将在花生抗原食物过敏模型中达到高潮，以确定这种环境如何因子控制疾病中的嗜酸性粒细胞功能。阐明肠道特异性信号如何影响嗜酸性粒细胞提高对其生物学的了解，并确定食物过敏中这些细胞的新型治疗靶标。此外，与该研究计划一起制定的培训计划将提供蓝图，以为我做好准备成功的学术生涯。在我的赞助商和共同赞助商的支持下，哈佛大学的协作环境，这项奖学金将使我能够为最终的独立粘膜免疫学中的位置。