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

基本信息

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
项目类别：
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

项目摘要

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引起的过敏反应中的作用抽象的食物过敏是一个日益严重的公共卫生问题，大约有 1500 万人受到影响美国。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。交界处粘附分子-A (JAM-A) 是一种紧密连接跨膜蛋白，在维持上皮细胞和内皮细胞的屏障功能。在小肠中，JAM-A 已被证明对上皮屏障功能很重要，并且缺乏 JAM-A (JAM-A-/-) 的小鼠肠道通透性增加。这些 JAM-A-/- 小鼠患上严重的食物过敏性疾病与 WT 动物相比，小动物固有层肥大细胞增多肠道，以及这些细胞的激活增加。在本提案中，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 Th2 反应导致肥大细胞在小肠中积聚。我们进一步计划针对易感动物中的肥大细胞，以减少过敏回复。为此，我们将中和干细胞因子 (SCF)，这是一种细胞因子，是细胞生长所需的细胞因子。外周组织肥大细胞的生长和激活。我们假设中和 SCF 将防止肥大细胞积聚并防止严重过敏反应。这些实验将有助于我们了解食物过敏反应中的屏障功能，例如并提供一种潜在的方法来减少这些反应的存在失调的屏障。