Regulation of Allergic Inflammation by Histamine

描述（由申请人提供）：细胞因子及其受体具有令人难以置信的调节多种细胞反应的能力，这对体内平衡和保护性免疫反应的控制很重要。越来越多地观察到细胞因子的背景或细胞特异性影响，但鉴于Jak和Stat家族内细胞内信号传导分子的有限库，调节这种影响的机制仍不清楚。最近，出现了细胞因子受体功能的“修饰剂”的概念，由此来自其他受体的信号可以通过细胞因子受体改变那些信号。我们令人兴奋的发现已经确定，组胺通过其受体H2 R起作用，是细胞对IL-4的反应所必需的。这种细胞因子在过敏反应中至关重要，我们已经证明H2 R KO小鼠具有消除IgE产生和嗜酸性粒细胞向肺的募集。在进一步研究这种相互作用中，我们已经确定造血和非造血细胞对IL-4具有组胺依赖性和独立性反应。我们假设H2 R作为来自IL-4受体的信号传导的修饰剂起作用，并且对于从IL-4的稳态功能转换为促过敏反应是必需的。我们建议检查这三个具体的目标，调查这一概念在小鼠模型和过敏患者。具体目标1将检查H2 R通过IL-4 R α链反应的功能要求（与Talal Chatila博士合作）。Specific Aim 2将使用最先进的mRNA深度测序（与Nadereh Jafari博士合作）绘制人类和小鼠细胞中组胺依赖性和非依赖性基因的独特图谱。具体目标3将研究组胺相关基因模式的发病机制，嗜酸性食管炎，并建立在我们现有的工作表明肥大细胞和组胺是重要的，在这种疾病。

DESCRIPTION (provided by applicant): Cytokines and their receptors have an incredible ability to regulate a diverse range of cellular responses, important for homeostasis and control of protective immune responses. Increasingly, context or cell-specific influences of cytokines are being observed but the mechanisms that regulate this remain unclear given the limited repertoire of intracellular signaling molecules within the Jak and Stat family. Recently, the concept of "modifiers" of cytokine receptor functions has emerged, whereby signals from other receptors can alter those through the cytokine receptor. Our exciting findings have established that histamine, acting via its receptor H2R, is necessary for cellular responses to IL-4. This cytokine is critically important in allergic responses and we have demonstrated that H2R KO mice have ablated IgE generation and eosinophil recruitment to the lungs. In studying this interaction further, we have identified that both hematopoietic and non-hematopoietic cells possess histamine-dependent and independent responsiveness to IL-4. We hypothesize that H2R functions as a modifier of signaling from the IL-4 receptor and is necessary for switching from the homeostatic functions of IL-4 to a pro- allergic response. We propose to examine this with three specific aims that investigate this concept in murine models and in allergic patients. Specific Aim 1 will examine the functional requirements for H2R on responses through the IL-4Ralpha chain (in collaboration with Dr Talal Chatila). Specific Aim 2 will map the unique profile of histamine-dependent and independent genes in human and murine cells using state-of-the-art mRNA deep sequencing (in collaboration with Dr Nadereh Jafari). Specific Aim 3 will examine histamine-associated gene patterns in the pathogenesis of eosinophilic esophagitis and build on our existing work demonstrating the mast cells and histamine are important in this disease.