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

接头分子 NHERF1 在调节哮喘和过敏反应中的新作用

• 批准号: 9172283
• 负责人: Hariharan Subramanian
• 金额: $ 24.9万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9172283
• 关键词: Accounting; Advisory Committees; Affect; Affinity; Age; Allergens; Allergic; Allergic Disease; Allergic Reaction; American; Anaphylatoxins; Anaphylaxis; Antigens; Asthma; Award; Binding; Biology; Cells; Cessation of life; Chemotactic Factors; Child; Chronic; Committee Members; Complement; Complement 3a; Development; Dimerization; Disease; Emergency department visit; Expenditure; Extrinsic asthma; Faculty; Family; Future; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GRK6 gene; Generations; Genetic; Health Care Costs; Healthcare; Heterotrimeric GTP-Binding Proteins; Histamine; Hospitalization; Human; IgE; IgE Receptors; Immune; In Vitro; Individual; Inflammation; Inflammation Mediators; Investigation; Lead; Leukotrienes; Lung Inflammation; Mediating; Mentors; Modeling; Mus; Passive Cutaneous Anaphylaxis; Pathogenesis; Pathway interactions; Pennsylvania; Phase; Phosphorylation; Phosphotransferases; Play; Prevalence; Process; Production; Protein Binding Domain; Proteins; Receptor Activation; Receptor Signaling; Regulation; Research; Resources; Role; Signal Pathway; Signal Transduction; Skin; Tertiary Protein Structure; Testing; Time; Training Programs; Tryptase; Universities; adapter protein; airway hyperresponsiveness; allergic response; base; cell type; chemokine; crosslink; cytokine; desensitization; in vivo; insight; mast cell; member; mouse model; neutrophil; novel; novel therapeutics; passive sensitization; receptor; receptor function; reconstitution; response; sodium-hydrogen exchanger regulatory factor; trafficking; transcription factor

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.

描述（由申请人提供）：过敏性疾病，如过敏反应和哮喘影响约10%的美国人，并可证明10岁以下儿童的致命性。重要的是，这些疾病每年导致> 500，000例住院治疗，医疗保健费用高达数十亿美元。过去30年的深入研究增加了我们对哮喘和其他过敏性疾病发病机制的了解。免疫球蛋白E（IgE）和肥大细胞在变态反应性疾病的发病机制中起着重要作用。IgE和过敏原/抗原引起的肥大细胞上IgE受体（FcεRI）的聚集导致炎症介质（如组胺和白三烯）通过称为“脱粒”的过程快速释放。肥大细胞还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流入，从而放大过敏反应。近年来研究发现，肥大细胞上表达的G蛋白偶联受体（GPCR）可增强IgE诱导的免疫应答。肥大细胞表达补体成分C3 a（C3 aR）的GPCR，肥大细胞特异性C3 aR活化增强IgE诱导的哮喘被动皮肤过敏反应（PCA）和气道高反应性（AHR）。C3 aR在其羧基端具有I类PSD-95/Dlg/Zo 1（PDZ）结合基序。Na+/H+交换调节因子（NHERF 1 -4）是PDZ结构域蛋白I类家族的成员，其结合几种GPCR并调节它们的运输和信号传导。最近，我证明了NHERF 1促进C3 a激活的肥大细胞的脱粒和趋化因子的产生。然而，NHERF 1不与C3 aR相互作用或影响C3 aR的运输。因此，NHERF 1可能利用一个独特的和一个未确定的途径来调节C3 aR信号在人类肥大细胞。此外，NHERF 1是否在体内调节C3 a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NHERF 1在体外调节人肥大细胞脱粒至C3 a的信号通路（目标1;指导阶段）。在独立阶段，我将研究NHERF 1在调节肥大细胞介导的体内反应，如PCA（目标2）和AHR和哮喘小鼠模型中的肺部炎症（目标3）中的作用。拟议研究的完成将有助于确定肥大细胞和体内过敏反应中NHERF 1的直接轴，并将为NHERF 1拮抗剂的未来发展提供见解，这些拮抗剂不仅可以靶向过敏反应和哮喘，还可以靶向其他肥大细胞介导的过敏性疾病。我的导师团队将由海达尔·阿里博士（主要导师）、约翰·D·Lambris（共同导师）和布鲁斯弗里德曼博士，雷诺A。Panettieri和Taku Kambayashi（科学咨询委员会），宾夕法尼亚大学（Penn）的所有教职员工和各自研究领域的知名专家。我将利用我的导师和科学咨询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专业知识，设施和资源的强大可用性来完成这项拟议的培训计划。