A novel role for the adapter molecule NHERF1 in regulating asthma and allergic re

描述（由申请人提供）：过敏反应和哮喘等过敏性疾病影响约10%的美国人，并且在10岁以下儿童中可被证明是致命的。重要的是，这些疾病每年造成50万人住院，医疗费用高达数十亿美元。在过去的30年里，激烈的研究增加了我们对哮喘和其他过敏性疾病发病机制的理解。免疫球蛋白E （IgE）和肥大细胞在过敏性疾病的发病机制中起着至关重要的作用。IgE和过敏原/抗原在肥大细胞上的IgE受体（FcϵRI）聚集导致炎症介质如组胺和白三烯的快速释放，这一过程被称为“脱粒”。肥大细胞还会释放大量的细胞因子和趋化因子，导致其他免疫细胞如中性粒细胞的涌入，从而放大过敏反应。近年来，肥大细胞上表达的G蛋白偶联受体（GPCR）增强了ige诱导的反应。肥大细胞表达补体成分C3a （C3aR）的GPCR，肥大细胞特异性C3aR激活可增强IgE诱导的哮喘被动皮肤过敏反应（PCA）和气道高反应性（AHR）。C3aR在其羧基端具有一类PSD-95/Dlg/Zo1 （PDZ）结合基序。Na+/H+交换调节因子（NHERF1-4）是PDZ结构域蛋白I类家族的成员，可结合多种GPCR并调节其转运和信号传导。最近，我证明了NHERF1促进C3a激活肥大细胞的脱颗粒和趋化因子的产生。然而，NHERF1不与C3aR的转运相互作用或影响。因此，NHERF1可能利用一种独特的、尚未确定的途径来调节人肥大细胞中的C3aR信号。此外，NHERF1是否在体内调节c3a介导的肥大细胞反应仍有待评估。该建议建立在我最近的观察基础上，旨在确定NHERF1在体外调节人肥大细胞脱颗粒到C3a的信号通路（Aim 1；指导期）。在独立阶段，我将研究NHERF1在调节肥大细胞介导的体内反应中的作用，如PCA（目的2）和哮喘小鼠模型中的AHR和肺部炎症（目的3）。这些研究的完成将有助于确定NHERF1在肥大细胞和体内过敏反应中的直接轴，并将为NHERF1拮抗剂的未来发展提供见解，这些拮抗剂不仅可以针对过敏反应和哮喘，还可以针对其他肥大细胞介导的过敏性疾病。我的指导团队将由Hydar Ali博士（主要导师），John D. Lambris博士（联合导师）和dr。Bruce Freedman、Raynold A. Panettieri和Taku Kambayashi（科学顾问委员会），他们都是宾夕法尼亚大学（Penn）的教职员工，也是各自研究领域的知名专家。我将利用我的导师和科学顾问委员会成员的智力优势和学术记录，以及宾夕法尼亚大学提供的强大的专业知识、设施和资源来完成这个拟议的培训计划。

DESCRIPTION (provided by applicant): Allergic diseases such as anaphylaxis and asthma affect ~10% of Americans, and can prove fatal in children under the age of 10. Importantly, these diseases accounts for >500,000 hospitalizations annually with billions of dollars in healthcare cost. Intense research over the past 30 years has increased our understanding of the pathogenesis of asthma and other allergic diseases. It has been well established that immunoglobulin E (IgE) and mast cells play critical roles in the pathogenesis of allergic disorders. The aggregation of IgE receptor (FcϵRI) on mast cells by IgE and allergen/antigen results in the rapid release of inflammatory mediators such as histamine and leukotrienes by a process termed as "degranulation". Mast cells also release copious amounts of cytokines and chemokines, which result in the influx of other immune cells such as neutrophils, thus amplifying the allergic response. It has been recently accepted that G protein coupled receptors (GPCR) expressed on mast cells potentiate IgE-induced responses. Mast cells express the GPCR for the complement component C3a (C3aR) and mast cell-specific C3aR activation enhance IgE induced passive cutaneous anaphylaxis (PCA) and airway hyperresponsiveness (AHR) in asthma. C3aR has a class I PSD-95/Dlg/Zo1 (PDZ) binding motif in its carboxyl-terminus. Na+/H+ exchanger regulatory factors (NHERF1-4) are members of the class I family of PDZ domain proteins that bind several GPCR and regulate their trafficking and signaling. Recently, I demonstrated that NHERF1 promotes degranulation and chemokine production in C3a activated mast cells. However, NHERF1 did not interact with or affect the trafficking of C3aR. Thus, NHERF1 probably utilizes a unique and an undetermined pathway to regulate C3aR signaling in human mast cells. Moreover, whether NHERF1 regulates C3a-mediated mast cell responses in vivo, remains to be evaluated. This proposal builds up on my recent observations and aims at identifying the signaling pathway through which NHERF1 regulates human mast cell degranulation to C3a in vitro (Aim 1; mentored phase). In the independent phase, I will examine the role of NHERF1 in regulating mast cell mediated in vivo responses such as PCA (Aim 2) and AHR and lung inflammation in a mouse model of asthma (Aim 3). The completion of the proposed studies will help define the direct axis of NHERF1 in mast cells and allergic responses in vivo and will provide insights into the future development of NHERF1 antagonists that can target not only anaphylaxis and asthma but also other mast cell mediated allergic diseases. My mentoring team will consist of Dr. Hydar Ali (primary mentor), Dr. John D. Lambris (co-mentor) and Drs. Bruce Freedman, Raynold A. Panettieri, and Taku Kambayashi (Scientific Advisory Committee), all faculty members at the University of Pennsylvania (Penn) and renowned experts in their respective fields of investigation. I will take advantage of the intellectual strength and academic track record of my mentors and scientific advisory committee members, and the robust availability of expertise, facilities, and resources offered at Penn to accomplish this proposed training program.