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

• 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
• 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

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， 食物蛋白质致敏。过敏性致敏促进了适应性免疫记忆的发展， 其特征在于产生IgE和IgG 1同种型抗体的抗原特异性Th 2细胞和B细胞。 IgE抗体与组织中的肥大细胞结合，这些IgE-肥大细胞单位能够快速而旺盛地诱导肥大细胞的增殖。 对少量食物抗原的回忆反应。临床前和临床研究强调了以下方面的重要性 IgE抗体在食物过敏的胃肠道表现，如腹痛、恶心和 呕吐，然而，对肥大细胞诱导引发这些症状的原因知之甚少。GDF 15是一种压力- 诱导的TGF-β细胞因子通过其受体介导厌食、条件性味觉厌恶和呕吐， GFRAL，位于最后区。GDF 15可以由1型和2型炎症诱导，但是其 在食物过敏中的作用尚不清楚。本提案的目的是研究GDF 15的作用- GFRAL信号在过敏小鼠中驱动对食物过敏原的回避行为。体内初步数据 食物过敏模型表明，GDF 15在过敏原攻击后以很大程度上 依赖于IgE、FceR 1a表达细胞和白三烯。使用小肠的qPCR和FISH 和结肠，我们发现结肠，但不是小肠， 细胞富含GDF 15转录物。有趣的是，GDF 15的急性药理学阻断改善了 两瓶偏好测试行为范例中的食物过敏原厌恶。这些数据表明，IgE- 介导的肥大细胞活化可能通过白三烯刺激结肠上皮GDF 15的产生， 驱使过敏原厌恶。为了检验这一假设，我们将追求两个目标。目标1将研究 GDF 15和GFRAL遗传缺陷对使用新产生的KO小鼠体内食物过敏原回避的影响 对食物过敏敏感的BALB/cJ背景菌株。GDF 15和GFRAL缺乏对肥大细胞的影响 还将描述实验性食物变态反应中细胞介导的免疫应答的特征。目标2将检查 IgE介导的肥大细胞活化如何启动实验性食物过敏中的GDF 15-GFRAL信号传导 小鼠遗传或免疫球蛋白E、肥大细胞和白三烯缺乏。肥大细胞依赖性 结肠上皮细胞转录组的变化也将被定量。这些研究将 增强我们对胃肠道2型免疫反应如何导致过敏原的理解 诱导的不适，并可能揭示新的目标，以防止并发症的口服免疫治疗（OIT）。 除了这些研究，申请人将完成一个先进的技术和理论的程序， 课程作业、临床选修课和科学技能建设。本申请中详细介绍的研究和培训 将准备他追求临床相关的基础科学事业作为一个医生科学家。