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: 8791428
• 负责人: Justine Tiglao Tigno-Aranjuez
• 金额: $ 13.07万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8791428
• 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; 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; 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; Pharmaceutical Preparations; Phase; Phosphotransferases; Play; Positioning Attribute; Pre-Clinical Model; Quality of life; RIPK2 gene; Receptor Signaling; Recurrence; Role; Signal Pathway; Signal Transduction; Simulate; Staging; Symptoms; Tertiary Protein Structure; Testing; Therapeutic; Translating; Tyrosine; Wheezing; airway hyperresponsiveness; airway inflammation; allergic response; alternative treatment; base; crosslink; cytokine; design; exposed human population; in vivo; inhibitor/antagonist; mast cell; meetings; monocyte; novel; receptor; research study; response; 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性皮质类固醇。虽然大多数哮喘患者通过这些药物的某些组合获得控制，但仍有一些患者没有从这些治疗中获益1，并且几乎没有替代治疗。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，但很少有生物制剂应用于临床（白三烯修饰剂2，3和抗IgE 4，5）。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这种差异可以通过治疗所针对的过敏性哮喘反应的阶段来解释。许多这些生物制剂，如抗IL-46，7、抗IL-58和抗IL-139，10治疗，针对的是在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。尽管我们对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度产生、气道高反应性、上皮下纤维化等）有一定的了解，但对哪些受体和信号通路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（NOD 2）是肽聚糖的先天性免疫受体11 -13，其最近也与2型应答的发展有关14 -16。当这种反应失调时，它们可以促进过敏性和哮喘性疾病的发展。RIP 2是一种激酶，其对于转导从NOD发出的信号是必需的217，18。通过确定RIP 2在对过敏原的初始应答过程中所起的作用并鉴定影响RIP 2活性的新机制，可以确定RIP 2的抑制是否可有效治疗过敏性哮喘。目前的建议旨在通过使用遗传和生物化学RIP 2激活标记来确定RIP 2激活是否发生在过敏原暴露的下游。我们还将探索一种新的机制，RIP 2可以潜在地被激活（NOD独立），以及这可能有助于哮喘的发病机制。最后，通过利用一种新的RIP 2过度激活的环境（瘙痒小鼠）和新的RIP 2抑制剂，我们将确定RIP 2抑制在哮喘动物模型中的疗效。