Mast cell regulation of food allergen induced malaise through GDF15-GFRAL signaling

肥大细胞通过 GDF15-GFRAL 信号调节食物过敏原引起的不适

基本信息

批准号：
10605915
负责人：
Nathaniel Dale Bachtel
金额：
$ 3.26万
依托单位：
YALE UNIVERSITY
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：
2023-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10605915
关键词：
Abdominal Pain Acute Affinity Allergens Allergic Allergic inflammation Anaphylaxis Anorexia Antibodies Antigens Automobile Driving B-Lymphocytes Basic Science Basophils Behavior Behavioral Behavioral Paradigm Binding Blocking Antibodies Body Weight decreased Capsaicin Cell Culture System Cells Cisplatin Clinical Clinical Research Colon Data Development Diarrhea Digestive System Disorders Disease Disease remission Eating Economic Burden Effectiveness Endowment Epithelial Cells Epithelium Food Food Hypersensitivity GDF15 gene Gastrointestinal tract structure Genetic Histamine Human IgE IgG1 Immune Immune response Immunologic Memory In Vitro Incidence Individual Inflammation Inflammatory Intestines Irritable Bowel Syndrome Knockout Mice Knowledge Lead Leukotrienes Malaise Mediating Mediator Metformin Modeling Molecular Biology Mus Nausea Nausea and Vomiting Nerve Neurons Nociceptors Nucleus solitarius Pathogenesis Pathway interactions Patients Physicians Play Predisposition Prevalence Production Proteins Pruritus Regulation Research Role Scientist Serum Shrews Signal Transduction Small Intestines Stress Structure of area postrema Symptoms T-Lymphocyte Taste aversion Technical Expertise Testing Th2 Cells Tissues Training Transcript Transforming Growth Factor beta Transgenic Mice Vascular Permeabilities Vasodilation Vomiting Work avoidance behavior behavior test career cell mediated immune response chemotherapy clinically relevant colonic crypt computer program cytokine desensitization food allergen food antigen gastrointestinal in vivo inhibitor mast cell mouse model nonhuman primate novel novel therapeutics oral immunotherapy pharmacologic preclinical study preference prevent programs receptor response skills transcriptome transcriptomics

项目摘要

Food allergy is associated with a hypersensitive type 2 immune response that develops following sensitization to food proteins. Allergic sensitization elicits the development of adaptive immune memory, characterized by antigen specific Th2 cells and B-cells which produce antibodies of the IgE and IgG1 isotypes. IgE antibodies bind to tissue resident mast cells, and these IgE-mast cell units enable a rapid and exuberant recall response to low quantities of food antigen. Pre-clinical and clinical studies underscore the importance of IgE antibodies in the gastrointestinal manifestation of food allergy, such as abdominal pain, nausea and vomiting, however what mast-cells induce to initiate these symptoms is poorly understood. GDF15 is a stress- induced TGF-b cytokine that mediates anorexia, conditioned taste aversion, and vomiting through its receptor, GFRAL, located on the area postrema. GDF15 can be induced by type 1 and type 2 inflammation, however its role in the context of food allergy is unclear. The objective of this proposal is to study the role of GDF15- GFRAL signaling in driving avoidance behavior to food allergens in allergic mice. Preliminary data in in vivo food allergy models demonstrates GDF15 is rapidly induced upon allergen challenge in a manner largely dependent on IgE, FceR1a expressing cells, and leukotrienes. Using qPCR and FISH of the small intestine and colon from food allergen challenged mice, we find that colonic, but not small intestinal, crypt epithelial cells are enriched in GDF15 transcripts. Interestingly, acute pharmacological blockade of GDF15 ameliorates food allergen aversion in a two-bottle preference test behavioral paradigm. This data suggests that IgE- mediated mast cell activation elicits colonic epithelial GDF15 production, potentially through leukotrienes, to drive allergen aversion. To test this hypothesis two aims will be pursued. Aim 1 will examine the effect of genetic deficiency of GDF15 and GFRAL on food allergen avoidance in vivo using newly generated KO mice on the food allergy susceptible BALB/cJ background strain. GDF15 and GFRAL deficiency’s effect on mast- cell mediated immune responses in experimental food allergy will also be characterized. Aim 2 will examine how IgE mediated mast cell activation initiates GDF15-GFRAL signaling in experimental food allergy using mice genetically or pharmacologically deficient in IgE, mast cells, and leukotrienes. Mast-cell dependent changes in the transcriptome of colonic epithelial cells will too be quantified. Together, these studies will enhance our understanding of how type 2 immune responses in the gastrointestinal tract lead to allergen induced malaise, and may reveal novel targets to prevent complications of oral immunotherapy (OIT). Alongside these studies, the applicant will complete a program of advanced technical and theoretical coursework, clinical electives, and scientific skill building. The research and training detailed in this application will prepare him to pursue a clinically relevant basic science career as a physician scientist.

食物过敏与过敏性 2 型免疫反应有关，该反应在以下情况下发生：对食物蛋白质的过敏引起适应性免疫记忆的发展，其特征是抗原特异性 Th2 细胞和 B 细胞产生 IgE 和 IgG1 同种型抗体。 IgE 抗体与组织驻留的肥大细胞结合，这些 IgE 肥大细胞单位能够快速而旺盛地对少量食物抗原的回忆反应强调了临床前和临床研究的重要性。 IgE抗体在食物过敏的胃肠道表现，如腹痛、恶心等呕吐，但是对于肥大细胞引发这些症状的原因知之甚少。诱导的 TGF-b 细胞因子通过其受体介导厌食、条件性味觉厌恶和呕吐， GFRAL，位于后部区域 GDF15 可由 1 型和 2 型炎症诱导，但其情况如何。该提案的目的是研究 GDF15- 在食物过敏中的作用。 GFRAL 信号驱动过敏小鼠对食物过敏原的回避行为的体内初步数据。食物过敏模型表明，GDF15 在过敏原挑战后迅速诱导，很大程度上取决于依赖于 IgE、FceR1a 表达细胞和白三烯，使用小肠的 qPCR 和 FISH。和来自食物过敏原攻击小鼠的结肠，我们发现结肠，而不是小肠，隐窝上皮细胞富含 GDF15 转录本，GDF15 的急性逻辑药理学阻断可改善。两瓶偏好测试行为范式中的食物过敏原厌恶该数据表明 IgE-。介导的肥大细胞激活可能通过白三烯诱导结肠上皮 GDF15 的产生，为了检验这一假设，目标 1 将检验其效果。 GDF15 和 GFRAL 遗传缺陷对新生 KO 小鼠体内食物过敏原回避的影响食物过敏易感 BALB/cJ 背景菌株 GDF15 和 GFRAL 缺乏对肥大的影响。目标 2 也将研究实验性食物过敏中细胞介导的免疫反应。 IgE 介导的肥大细胞激活如何在实验性食物过敏中启动 GDF15-GFRAL 信号传导遗传上或药理学上缺乏 IgE、肥大细胞和肥大细胞依赖性的小鼠。结肠上皮细胞转录组的变化也将被量化。增强我们对胃肠道 2 型免疫反应如何导致过敏原的理解引起的不适，并可能揭示预防口服免疫疗法（OIT）并发症的新靶点。除了这些研究之外，申请人还将完成高级技术和理论课程本申请中详细介绍了课程作业、临床选修课和科学技能培养。将为他作为一名医师科学家从事临床相关的基础科学职业做好准备。