Phenotypic and functional plasticity of mast cells in homeostasis and allergy

项目总结 过敏性疾病在全球范围内的流行程度正在上升。现有的过敏症增加了罹患 同一人的另一种过敏反应，大约80%的特应性皮炎儿童发生 哮喘或过敏性鼻炎在晚年的一个过程中被称为“特应性进行曲”。肥大细胞是长寿细胞 这对过敏反应和病情进展很重要。肥大细胞的先天记忆是一个新的概念 最初的激活事件决定了细胞的功能命运和未来的反应。最近的研究已经定义了 单核细胞和NK细胞中的“先天记忆”，通过初始激活改变对 不同的第二刺激(即训练)。在两篇里程碑式的《科学》论文中，研究小组表明，先天记忆是 在表观遗传水平上进行调节，并导致这些细胞的新陈代谢和炎症潜能改变。 肥大细胞是寿命更长的细胞，特应性患者通常1)多敏化，2)反复经历 一幕幕的反应性。因此，我假设肥大细胞可能同样经历了表型改变。 这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 肥大细胞对不同的IgE/抗原组合经历了反复的激活事件，定义了一个 经过训练的肥大细胞的转录签名。从机制上讲，这种信号包括调节类型的基因。 2免疫反应、细胞黏附、血管通透性和存活率。我建议把重点放在 机制(表观遗传、代谢等)对这一现象负有责任，如果其他已知的 肥大细胞刺激是诱导这种记忆特征的电缆。我们特别建议将重点放在白介素类 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 最显著的是，经过训练的肥大细胞中的基因表达上调。我们的实验室是第一个公布IL-33是 由肥大细胞表达，但其功能后果尚不清楚。 我是西北大学过敏免疫学系二年级的医学博士研究生。 研究生院。我正在训练的环境非常适合我学习基础知识和 过敏性疾病背景下肥大细胞先天记忆的科学和临床方面。这项建议符合 我的职业目标和该机构的使命，因为它试图了解细胞机制 推动了目前还没有有效治疗方法的特应性进行曲。

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.