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Interaction of histamine-releasing factor with immunoglobulins in asthma

哮喘中组胺释放因子与免疫球蛋白的相互作用

基本信息

批准号：
9298705
负责人：
TOSHIAKI KAWAKAMI
金额：
$ 47.52万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9298705
关键词：
Address Affect Affinity Allergic Disease Allergic Reaction Animal Experiments Asthma Base Sequence Basophils Binding Binding Sites Cell Cycle Progression Clinical Clinical Research Complement Complex Crystallization Developed Countries Development Drug Design Embryo Epidemic Fab Immunoglobulins Future Genes Human IgE IgE Receptors Immunoglobulin G Immunoglobulins In Vitro Intranasal Administration Irrigation Knockout Mice Knowledge Liquid substance Lung Lung Inflammation Malignant - descriptor Maps Modeling Molecular Molecular Cloning Molecular Profiling Mus NMR Spectroscopy Pathogenesis Pathogenicity Patients Peptides Phase Prevalence Preventive Property Proteins Pseudogenes Publications Role Sampling Stem cells TPT1 gene Testing Therapeutic Transgenic Mice Translating Work X-Ray Crystallography airway inflammation aptamer asthmatic cancer stem cell cytokine experimental study extracellular gene product in vivo inhibitor/antagonist innovation insight mammalian genome mast cell mouse model novel novel therapeutics overexpression prevent public health relevance receptor skin hypersensitivity stemness synthetic construct

项目摘要

DESCRIPTION (provided by applicant): The prevalence of asthma and allergic diseases has been dramatically increasing for the last few decades and has reached epidemic proportions in industrialized countries. Current therapy is not preventive or curative. Thus, novel therapeutic strategies are urgently needed. Histamine-releasing factor (HRF) can activate mast cells and basophils in an IgE-dependent manner. As its secretion was found in bodily fluids during late-phase allergic reactions, HRF has been implied in allergic diseases including asthma. How HRF is involved in allergic reactions had remained enigmatic for two decades. However, our 2012 study changed this situation by identifying a subset of IgE and IgG molecules as HRF receptors; mapping of the immunoglobulin (Ig) Fab-binding sites within the HRF molecule led to the discovery of HRF sequence-based inhibitors, N19 and H3 peptides, which competitively blocked HRF-Ig interactions; administration of these inhibitors drastically reduced airway inflammation in mast cell- and IgE-dependent models of asthma; intranasal administration of na�ve mice with HRF caused airway inflammation in an Fc�RI (= high-affinity IgE receptor) and mast cell-dependent manner. In this project, to gain more structural insights into HRF-Ig interactions, (i) we will identify the molecular signature of HRF-reactive IgE and IgG molecules, and (ii) analyze structural and dynamic features for HRF-Ig interactions at atomic and submolecular levels by X-ray crystallography and NMR spectroscopy. If HRF inhibitors should ever be used in a clinical setting, they would initially be tested on patients with abundant HRF-Ig interactions. To mimic such conditions, (iii) we will test whether and what HRF inhibitors are effective to treat airway inflammation in transgenic mice overexpressing HRF in the lung or HRF-reactive IgE. Several HRF-related pseudogenes are present in human and other mammalian genomes. Therefore, (iv) we will test whether their gene products affect HRF functions. Knowledge to be gained through this project will enrich our understanding of HRF-Ig interactions and the pathogenic roles of HRF-Ig interactions in asthma models, which will be crucial for our future clinical study.

描述（由申请人提供）：在过去的几十年里，哮喘和过敏性疾病的患病率急剧上升，在工业化国家已达到流行病的程度。目前的治疗既不能预防也不能治愈。因此，迫切需要新的治疗策略。组胺释放因子（HRF）以ige依赖的方式激活肥大细胞和嗜碱性细胞。由于在晚期过敏反应时在体液中发现其分泌，HRF被认为与包括哮喘在内的过敏性疾病有关。二十年来，HRF是如何参与过敏反应的一直是个谜。然而，我们2012年的研究通过确定IgE和IgG分子的一个子集作为HRF受体改变了这种情况；HRF分子内免疫球蛋白（Ig） fab结合位点的定位导致了基于HRF序列的抑制剂N19和H3肽的发现，它们竞争性地阻断了HRF-Ig的相互作用；在肥大细胞和ige依赖的哮喘模型中，施用这些抑制剂可显著减少气道炎症；经鼻给药HRF小鼠可引起Fc - RI（高亲和IgE受体）和肥大细胞依赖方式的气道炎症。在这个项目中，为了获得更多关于HRF-Ig相互作用的结构见解，(i)我们将识别hrf反应性IgE和IgG分子的分子特征，（ii）通过x射线晶体学和核磁共振波谱分析HRF-Ig相互作用在原子和亚分子水平上的结构和动态特征。如果HRF抑制剂应该用于临床，它们将首先在有大量HRF- ig相互作用的患者身上进行测试。为了模拟这种情况，（iii）我们将测试HRF抑制剂是否以及哪些抑制剂对肺中过度表达HRF或HRF反应性IgE的转基因小鼠的气道炎症有效。在人类和其他哺乳动物基因组中存在几种与hrf相关的假基因。因此，（iv）我们将测试它们的基因产物是否影响HRF功能。通过该项目获得的知识将丰富我们对HRF-Ig相互作用以及HRF-Ig相互作用在哮喘模型中的致病作用的理解，这对我们未来的临床研究至关重要。