Microbiota regulation of intestinal eosinophils

微生物群对肠道嗜酸性粒细胞的调节

• 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
• 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

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 食物过敏的特点是对无害食物抗原的异常免疫激活，并影响 占美国人口的 5-8%。目前的护理标准仍然仅限于避免过敏原，这表明 需要新的治疗途径。一种有希望的方法是控制过敏的发生 由辅助 T 2 (Th2) 细胞介导的炎症反应。在食物过敏中，Th2 细胞由抗原诱导 在肠道中呈现树突状细胞 (DC)，而树突状细胞又被肠道嗜酸性粒细胞（一种先天免疫）激活 与 2 型免疫相关的细胞类型。因此，调节肠道嗜酸性粒细胞是一种有前途的方法。 在过敏反应开始时进行干预的点。虽然肠道含有最大的 体内嗜酸性粒细胞群体，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微生物群，这至关重要 塑造肠道免疫细胞。有趣的是，无菌（GF）小鼠或小鼠体内的微生物群受到破坏 小鼠和人类的抗生素治疗也与病情恶化和发病率增加有关 食物过敏，但其机制尚不完全清楚。我推测微生物群调节肠道 嗜酸性粒细胞及其在食物过敏中的功能。我提出的肠道嗜酸性粒细胞调节机制研究 通过微生物群将最终形成花生抗原食物过敏模型，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将 提高对其生物学的了解，并确定这些细胞在食物过敏中的新治疗靶点。 此外，与本研究计划一起制定的培训计划将为我提供一个蓝图，帮助我做好准备 成功的学术生涯。在我的赞助商和共同赞助商的支持下，我们在创新和 在哈佛的协作环境中，这项奖学金将使我为最终的独立做好准备 在粘膜免疫学中的地位。