Phenotypic and functional plasticity of mast cells in homeostasis and allergy

肥大细胞在稳态和过敏中的表型和功能可塑性

• 批准号: 9888325
• 负责人: Krishan Dilip Chhiba
• 金额: $ 2.64万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2020-05-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9888325
• 关键词: Affect; Allergic; Allergic Disease; Allergic rhinitis; Anti-Inflammatory Agents; Antibodies; Antigens; Asthma; Atopic Dermatitis; Autoimmunity; Automobile Driving; Basic Science; Bioinformatics; Cell Adhesion; Cell Shape; Cells; ChIP-seq; Child; Chronic; Clinical; Collaborations; Core Facility; Data; Development; Disease; Elements; Environment; Epigenetic Process; Epithelial; Epithelium; Event; Exhibits; Experimental Models; Food Hypersensitivity; Future; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Goals; Healthcare; Hepatitis B e Antigens; Histones; Homeostasis; Hypersensitivity; IgE; Immune; Immune response; Immunology; Individual; Infection; Infiltration; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukins; Life; Link; Lung; Lung diseases; Malignant Neoplasms; Mediating; Memory; Metabolic; Metabolic Pathway; Metabolism; Mission; Modification; Mus; Natural Killer Cells; Nature; Paper; Patients; Phenotype; Population; Prevalence; Process; Proteomics; Publishing; Quality of life; Recurrence; Risk; Role; Schools; Science; Severities; Signal Transduction; Stimulus; Symptoms; Testing; Tissues; Training; Universities; Vascular Permeabilities; Work; allergic response; beta-Glucans; career; cytokine; defined contribution; doctoral student; effective therapy; eosinophil; experience; functional plasticity; in vivo Model; mass spectrometer; mast cell; monocyte; novel; prevent; response; transcriptome sequencing; wound healing

PROJECT SUMMARY Allergic diseases are increasing in prevalence worldwide. Existing allergy increases the risk for developing another allergy in the same individual, with approximately 80% of children with atopic dermatitis developing asthma or allergic rhinitis later in life in a process known as the “atopic march”. Mast cells are long-lived cells that are important for allergic responses and progression. Innate memory in mast cells is the novel concept that initial activation events shape the cell's functional fate and future responses. Recent studies have defined “innate memory” in monocytes and NK cells, whereby initial activation alters the phenotype of response to a different second stimulus (i.e. training). In two landmark Science papers, groups show that innate memory is regulated at the epigenetic level and results in an altered metabolism and inflammatory potential of these cells. Mast cells are longer-lived cells, and atopic patients are often 1) poly-sensitized, and 2) experiencing repeated episodes of reactivity. Therefore, I hypothesize that mast cells might similarly undergo phenotypic alterations that reflect a “memory” of prior activation events, or training. My preliminary data using RNAseq profiling of mast cells undergoing recurrent activation events to different IgE/antigen combinations has defined a transcriptional signature for trained mast cells. Mechanistically, this signature includes genes that regulate type 2 immune responses, cell adhesion, vascular permeability, and survival. I am proposing to focus on the mechanisms (epigenetic, metabolic, etc.) that are responsible for this phenomenon as well as if other known mast cell stimuli are cable of inducing this memory signature. We specifically propose to focus on Interleukin 33 (IL-33), a cytokine that has been extensively linked to allergy and severe respiratory diseases, since it is the most significantly up-regulated genes in trained mast cells. Our lab was the first to publish that IL-33 is expressed by mast cells, but the functional consequences of this remains unclear. I am a MD/PhD student at Northwestern University in the Division of Allergy-Immunology in the second year of graduate school. The environment in which I am training is perfectly suited for me to study both the basic science and clinical aspects of mast cell innate memory in the context of allergic diseases. This proposal aligns with my career goals and the mission of the agency because it seeks to understand the cellular mechanisms driving the atopic march for which there are no effective therapies.

项目摘要 过敏性疾病在世界范围内的流行率正在增加。现有的过敏症会增加发展的风险 在同一个体中发生另一种过敏，大约80%的特应性皮炎儿童 哮喘或过敏性鼻炎在以后的生活中在称为“特应性进行曲”的过程中发生。肥大细胞是长寿细胞 对过敏反应和进展很重要。肥大细胞的先天记忆是一个新概念 最初的激活事件塑造了细胞的功能命运和未来的反应。最近的研究表明， 单核细胞和NK细胞中的“先天记忆”，由此初始激活改变了对免疫应答的表型。 不同的第二刺激（即训练）。在两篇具有里程碑意义的《科学》论文中，研究小组表明， 在表观遗传水平上受到调节，并导致这些细胞的代谢和炎症潜能改变。 肥大细胞是寿命较长的细胞，特应性患者通常1）多致敏，2）经历反复的 反应性发作。因此，我推测肥大细胞可能同样经历表型改变， 其反映了先前激活事件或训练的“记忆”。我使用RNAseq分析的初步数据 经历对不同IgE/抗原组合的反复激活事件的肥大细胞已经定义了一种 肥大细胞的转录特征从机制上讲，这种特征包括调节类型的基因， 2免疫应答、细胞粘附、血管通透性和存活。我建议把重点放在 机制（表观遗传、代谢等）造成这种现象的原因，以及其他已知的 肥大细胞刺激可以诱导这种记忆信号。我们特别建议关注白细胞介素 33（IL-33），一种与过敏和严重呼吸道疾病广泛相关的细胞因子，因为它是 在训练的肥大细胞中最显著上调的基因。我们的实验室是第一个发表IL-33是 由肥大细胞表达，但其功能后果仍不清楚。 我是西北大学过敏免疫学系的一名医学博士/博士生， 研究生院我训练的环境非常适合我学习基本的 在过敏性疾病背景下肥大细胞先天记忆的科学和临床方面。该提案与 我的职业目标和机构的使命，因为它试图了解细胞机制， 导致了目前尚无有效治疗方法的特应性疾病