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）：过敏反应和哮喘等过敏性疾病影响约 10% 的美国人，并且可能对 10 岁以下儿童致命。重要的是，这些疾病每年导致超过 500,000 人住院，医疗费用高达数十亿美元过去 30 年的深入研究加深了我们对哮喘和其他过敏性疾病发病机制的了解，现已明确免疫球蛋白 E (IgE) 和哮喘的发病机制。肥大细胞在过敏性疾病的发病机制中发挥着关键作用，IgE 和过敏原/抗原导致 IgE 受体 (FcϵRI) 在肥大细胞上的聚集，通过称为“脱颗粒”的过程导致组胺和白三烯等炎症介质的快速释放。肥大细胞还释放大量细胞因子和趋化因子，导致中性粒细胞等其他免疫细胞涌入，从而放大免疫细胞。最近人们认为，肥大细胞上表达的 G 蛋白偶联受体 (GPCR) 会增强 IgE 诱导的反应，肥大细胞表达补体成分 C3a (C3aR) 的 GPCR，并且肥大细胞特异性 C3aR 激活会增强 IgE 诱导的被动反应。哮喘中的皮肤过敏反应 (PCA) 和气道高反应性 (AHR) C3aR 具有 I 类 PSD-95/Dlg/Zo1。其羧基末端的 (PDZ) 结合基序 (NHERF1-4) 是 PDZ 结构域蛋白 I 类家族的成员，可结合多个 GPCR 并调节其运输和信号转导。然而，NHERF1 不与 C3aR 相互作用或影响 C3aR 的运输，因此，NHERF1 可能利用了一种独特的机制。此外，NHERF1 是否在体内调节 C3a 介导的肥大细胞反应还有待评估。该提议建立在我最近的观察基础上，旨在确定 NHERF1 调节人类的信号传导途径。体外肥大细胞脱颗粒为 C3a（目标 1；指导阶段） 在独立阶段，我将研究 NHERF1 在调节肥大细胞介导的体内反应（例如 PCA）中的作用。 （目标 2）以及哮喘小鼠模型中的 AHR 和肺部炎症（目标 3）。拟议研究的完成将有助于确定肥大细胞中 NHERF1 的直轴和体内过敏反应，并将为未来的发展提供见解。 NHERF1 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）和 John D. Lambris 博士（共同导师）组成。以及 Bruce Freedman 博士、Raynold A. Panettieri 博士和 Taku Kambayashi 博士（科学顾问委员会），以及宾夕法尼亚大学（宾夕法尼亚大学）的所有教员和各自研究领域的知名专家，我将利用他们的智力优势和研究成果。我的导师和科学咨询委员会成员的学术记录，以及宾夕法尼亚大学为完成这项拟议的培训计划提供的强大的专业知识、设施和资源。