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

• 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
• 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

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包括支气管扩张剂和吸入皮质类固醇。虽然大多数哮喘患者通过这些药物的某种组合得到了控制，但仍有一些人没有从这些治疗中获益，而且他们几乎没有其他的治疗方法。这表明需要开发新的哮喘治疗方法。尽管开发了许多靶向治疗哮喘的生物制剂，但很少有转化为临床的（白三烯修饰剂2,3和抗ige4,5）。在临床前模型中发现的有效疗法与在哮喘患者中实际有益的疗法之间的差异，可能是由治疗所针对的过敏性哮喘反应的阶段来解释的。许多生物制剂，如抗il - 46,7、抗il -58和抗il -139治疗，都是针对过敏反应后期产生的分子。通过研究在过敏反应开始时发生的事件，我们可能更好地理解并能够为临床收益操纵免疫反应。尽管我们知道下游的过敏和哮喘后遗症（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），但很少知道哪些受体和信号通路在启动过敏反应中是重要的。核苷酸寡聚结构域2 （NOD2）是肽聚糖11-13的先天免疫受体，最近也被认为与2型反应的发展有关14-16。当这些反应失调时，它们会促进过敏和哮喘疾病的发展。RIP2是一种激酶，对nod217,18发出的转导信号至关重要。通过确定RIP2在对过敏原的初始反应中所起的作用，以及确定RIP2活性受到影响的新机制，人们可以确定抑制RIP2是否对过敏性哮喘的治疗有效。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RIP2可能被激活（NOD独立）的新机制，以及这可能如何促进哮喘的发病机制。最后，通过利用一种新的RIP2过激活设置（瘙痒小鼠）和新型RIP2抑制剂，我们将确定RIP2抑制在哮喘动物模型中的效果。