Role of epithelial barrier function in food-induced anaphylaxis

上皮屏障功能在食物引起的过敏反应中的作用

• 批准号: 10655689
• 负责人: Catherine Mary Ptaschinski
• 金额: $ 39.46万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655689
• 关键词: 18 year old; Adverse effects; Affect; Allergens; Allergic; Allergic Disease; Allergic Reaction; Anaphylaxis; Animal Model; Animals; Antigens; Bacteria; Binding; Cell Count; Cells; Child; Data; Defect; Dendritic Cells; Desmosomes; Development; Diagnosis; Disease; Emergency Care; Endothelium; Epithelial Attachment; Epithelial Cells; Epithelium; Exhibits; Food; Food Hypersensitivity; Goals; Growth; Hospitalized Child; IgE; Immune; Immune response; Immune system; Immunity; Incidence; Ingestion; Integral Membrane Protein; Intestinal Content; Intestinal permeability; Intestines; Lamina Propria; Maintenance; Mediating; Methods; Minority; Modeling; Mucous Membrane; Mus; Nutrient; Organism; Patients; Peripheral; Persons; Play; Population; Predisposition; Proteins; Public Health; Reaction; Regulation; Research; Role; Serious Adverse Event; Serum; Severities; Side; Small Intestines; Stem Cell Factor; Structure; TNFSF4 gene; Tamoxifen; Therapeutic; Tight Junctions; Time; Tissues; United States; adherent junction; allergic response; cytokine; experimental study; food allergen; food antigen; food challenge; gastrointestinal; immune activation; immunoreaction; intestinal barrier; intestinal epithelium; junctional adhesion molecule; mast cell; microbial; mouse development; mouse model; oral immunotherapy; particle; prevent; response; success; uptake; villin

Role of epithelial barrier function in food-induced anaphylaxis ABSTRACT Food allergy is a growing public health problem with approximately 15 million people affected in the United States. In allergic food disease, IgE on mast cells bind to ingested antigens leading to the activation and degranulation of mast cells. In order to activate mast cells, food antigens must pass through the intestinal epithelial barrier and activate cells in the lamina propria. Junction Adhesion Molecule-A (JAM-A) is a tight junction transmembrane protein that plays a major role in the maintenance of barrier function in epithelia and endothelia. In the small intestine, JAM-A has been shown to be important in epithelial barrier function, and mice that lack JAM-A (JAM-A-/-) have increased intestinal permeability. These JAM-A-/- mice develop severe food allergic disease compared to WT animals and have increased mast cells in the lamina propria of the small intestine, as well as increased activation of these cells. In this proposal, we aim to better understand the role of JAM-A in the development of severe food allergy, including the induction of a strong Th2 response that results in mast cell accumulation in the small intestine. We further plan to target those mast cells in susceptible animals with the aim of decreasing the allergic response. To do this, we will neutralize stem cell factor (SCF), a cytokine that is required for the growth and activation of peripheral tissue mast cells. We hypothesize that neutralizing SCF will prevent mast cell accumulation and protect from severe anaphylactic reactions. These experiments will contribute to our understanding of barrier function in food allergic reactions, as well as provide a potential method for decreasing these reactions in the presence of a dysregulated barrier.

上皮屏障功能在食物过敏反应中的作用 摘要 食物过敏是一个日益严重的公共卫生问题， 美国的在过敏性食物疾病中，肥大细胞上的IgE与摄入的抗原结合，导致 肥大细胞的活化和脱粒。为了激活肥大细胞，食物抗原必须 穿过肠上皮屏障并激活固有层中的细胞。结 粘附分子-A（JAM-A）是一种紧密连接跨膜蛋白，在细胞间粘附中起主要作用。 维持上皮和内皮的屏障功能。在小肠中，JAM-A具有 已被证明对上皮屏障功能很重要，而缺乏JAM-A（JAM-A-/-）的小鼠 增加了肠道通透性。这些JAM-A-/-小鼠发生严重的食物过敏性疾病 与野生型动物相比， 肠，以及增加这些细胞的激活。在这一建议中，我们的目标是更好地 了解JAM-A在严重食物过敏发展中的作用，包括诱导 强烈的Th 2反应导致肥大细胞在小肠中积聚。我们进一步 计划在易感动物中靶向这些肥大细胞，目的是减少过敏性 反应为此，我们将中和干细胞因子（SCF），一种细胞因子， 周围组织肥大细胞的生长和活化。我们假设中和SCF将 防止肥大细胞积聚，防止严重的过敏反应。这些 实验将有助于我们理解食物过敏反应中的屏障功能， 并提供了一种潜在的方法， 失调的屏障