The Role of RIP2 Kinase in the Pathogenesis of Allergic Asthma

RIP2激酶在过敏性哮喘发病机制中的作用

基本信息

批准号：
9127317
负责人：
Justine Tiglao Tigno-Aranjuez
金额：
$ 24.7万
依托单位：
UNIVERSITY OF CENTRAL FLORIDA
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 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9127317
关键词：
Acute Adrenal Cortex Hormones Affect Agonist Allergens Allergic Allergic Reaction Animal Model Antibodies Antigen-Presenting Cells Antigens Area Asthma Binding Biochemical Biological Biological Markers Breathing Bronchodilator Agents Cells Characteristics Chronic Clinic Clinical Combination Medication Complement Dendritic Cells Development Diagnostic Disease Epithelial Cells Event Exhibits Exposure to Extrinsic asthma FDA approved Family member Fibrosis Future Genetic Goals IgE Immune response Immunity Immunologic Receptors In Vitro Inflammation Mediators Intervention Knockout Mice Knowledge Laboratories Leukotrienes Ligands Lung Lung diseases Mediator of activation protein Mentors Modeling Molecular Mucous body substance Mus Natural Immunity Nucleotides Pathogenesis Pathology Pathway interactions Peptidoglycan Phase Phosphotransferases Play Positioning Attribute Pre-Clinical Model Quality of life RIPK2 gene Receptor Signaling Recurrence Role Signal Pathway Signal Transduction Staging Symptoms Tertiary Protein Structure Testing Therapeutic Translating Tyrosine Wheezing airway hyperresponsiveness airway inflammation allergic response alternative treatment asthmatic base crosslink cytokine design exposed human population in vivo inhibitor/antagonist mast cell meetings monocyte novel novel therapeutics personalized medicine predictive marker receptor research study response targeted treatment tool ubiquitin-protein ligase upstream kinase

项目摘要

DESCRIPTION (provided by applicant): The most widely used treatments for asthma consist of bronchodilators and inhaled corticosteroids. Although majority of asthmatics achieve control with some combination of these medications, there are those who receive no benefit from these treatments1 and for whom few alternative treatments remain. This indicates the need for the development of novel asthma therapies. Despite the numerous biologic agents developed which are targeted for the treatment of asthma, few have translated into the clinic (leukotriene modifiers2, 3 and anti- IgE4, 5). This disparity between what therapies are found to be efficacious in preclinical models and those which are actually beneficial in asthmatics, might be explained by the stage in the allergic asthmatic response being targeted by the therapy. A number of these biologicals such as anti-IL-46, 7, anti-IL-58, and anti-IL-139, 10 therapy, are directed at molecules which are generated late in the allergic reaction. By studying events which occur during the initiation of an allergic response, we might better understand and be able to manipulate immune responses for clinical gain. In spite of our knowledge of the downstream allergic and asthmatic sequelae (release of cytokines and inflammatory mediators leading to mucus overproduction, airway hyperreactivity, subepithelial fibrosis etc), little is known about which receptors and signaling pathways are important in initiating an allergic response. Nucleotide Oligomerization Domain 2 (NOD2) is an innate immune receptor for peptidoglycan11-13 which has also recently been implicated in the development of type-2 responses14-16. When such responses are dysregulated, they can promote the development of allergic and asthmatic disease. RIP2 is a kinase which is essential for transducing signals emanating from NOD217, 18. By determining the role which RIP2 plays during the initial response to allergens and identifying novel mechanisms by which RIP2 activity is influenced, one can ascertain if inhibition of RIP2 may be efficacious for the treatment of allergic asthma. The current proposal seeks to determine if RIP2 activation occurs downstream of allergen exposure through the use of genetic and biochemical RIP2 activation markers. We will also explore a novel mechanism by which RIP2 can potentially be activated (NOD independent) and how this may contribute to the pathogenesis of asthma. Lastly, by utilizing a novel setting of RIP2 overactivation (the Itchy mouse) and novel RIP2 inhibitors, we will determine the efficacy of RIP2 inhibition in animal models of asthma.

描述（由申请人提供）：最广泛使用的哮喘治疗方法包括支气管扩张剂和吸入皮质类固醇。尽管大多数哮喘患者通过这些药物的某种组合获得了控制，但有些人并没有从这些治疗中获益1，并且几乎没有其他治疗方法可供选择。这表明需要开发新型哮喘疗法。尽管开发了许多针对哮喘治疗的生物制剂，但很少有药物转化为临床（白三烯调节剂2、3和抗IgE4、5）。在临床前模型中发现有效的疗法与实际上对哮喘患者有益的疗法之间的这种差异可能可以通过治疗所针对的过敏性哮喘反应的阶段来解释。许多此类生物制剂，例如抗 IL-46, 7、抗 IL-58 和抗 IL-139, 10 疗法，均针对过敏反应后期产生的分子。通过研究过敏反应开始期间发生的事件，我们可以更好地理解并能够操纵免疫反应以获得临床收益。尽管我们了解下游过敏和哮喘后遗症（细胞因子和炎症介质的释放导致粘液过量产生、气道高反应性、上皮下纤维化等），但对于哪些受体和信号传导途径在引发过敏反应中起重要作用却知之甚少。核苷酸寡聚化结构域 2 (NOD2) 是肽聚糖的先天免疫受体 11-13，最近也与 2 型反应的发展有关 14-16。当这种反应失调时，就会促进过敏和哮喘疾病的发展。 RIP2 是一种激酶，对于转导 NOD217 发出的信号至关重要，18。通过确定 RIP2 在对过敏原的初始反应中所起的作用并确定影响 RIP2 活性的新机制，可以确定抑制 RIP2 是否有效用于治疗过敏性哮喘。目前的提案旨在通过使用遗传和生化 RIP2 激活标记来确定 RIP2 激活是否发生在过敏原暴露的下游。我们还将探索一种可能激活 RIP2（独立于 NOD）的新机制，以及这如何促进哮喘的发病机制。最后，通过利用 RIP2 过度激活的新环境（发痒小鼠）和新型 RIP2 抑制剂，我们将确定 RIP2 抑制在哮喘动物模型中的功效。