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：
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
项目类别：
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

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）：哮喘最广泛使用的治疗方法由支气管扩张剂和吸入的皮质类固醇组成。尽管大多数哮喘患者通过这些药物的某种结合来控制控制，但有些人没有从这些治疗中获得任何好处1，而几乎没有其他替代治疗。这表明需要发展新型哮喘疗法。尽管开发了许多用于治疗哮喘的生物学毒剂，但很少有人转化为诊所（白三烯修饰剂2、3和抗IGE4、5）。在临床前模型中发现哪种疗法与实际上有益于哮喘的疗法之间的这种差异可能是通过治疗靶向的过敏性哮喘反应的阶段来解释的。这些生物学中的许多生物学，例如抗IL-46、7，抗IL-58和抗IL-139，10疗法，是针对过敏反应后期产生的分子。通过研究启动过敏反应期间发生的事件，我们可以更好地理解并能够操纵免疫反应以获得临床增益。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，导致粘液过量产生粘液过量，气道高反应性，上皮纤维化等），关于哪些受体和信号通路在启动过敏反应方面很重要。核苷酸寡聚结构域2（NOD2）是肽聚糖11-13的先天免疫受体，最近也与2型响应的发展有关14-16。当这种反应失调时，它们可以促进过敏和哮喘疾病的发展。 RIP2是一种激酶，对于从NOD217，18发出的信号至关重要。用于治疗过敏性哮喘。当前的提案旨在通过使用遗传和生化RIP2激活标记来确定过敏原暴露的下游RIP2激活。我们还将探索一种新的机制，可以通过该机制激活RIP2（NOD独立），以及这可能如何有助于哮喘的发病机理。最后，通过利用RIP2过度活化的新型设置（发痒的小鼠）和新型的RIP2抑制剂，我们将确定RIP2抑制作用在哮喘动物模型中的疗效。