Targeting CCL28 as therapy for obstructive lung disease

靶向 CCL28 治疗阻塞性肺病

基本信息

批准号：
9282770
负责人：
Brian F Volkman
金额：
$ 38.5万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-15 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9282770
关键词：
Address Affect Affinity Agonist Asthma Binding Binding Sites Biological Biological Assay Cells Child Chronic Obstructive Airway Disease Country Data Databases Dendritic Cells Development Diagnosis Disease Docking Dose Family Future G-Protein-Coupled Receptors GPR2 gene Health Human IgE IgE Receptors In Vitro Infection Inflammation Inflammatory Interleukin-13 Lead Leukocytes Ligands Lung Lung Inflammation Lymphocyte Measures Mediating Metaplasia Modeling Modernization Mucous body substance Mus Mutagenesis N-terminal NMR Spectroscopy Obstructive Lung Diseases Paramyxoviridae Paramyxovirus Pathway interactions Patients Persons Pharmacotherapy Physiological Population Preclinical Testing Prevalence Process Production Proteins Public Health Receptor Activation Recruitment Activity Respiratory Tract Infections Respiratory syncytial virus Risk Role Route Schools Sendai virus Severity of illness Signal Transduction Site Structure Surface Symptoms Testing Th2 Cells Therapeutic Up-Regulation Viral Viral Respiratory Tract Infection Virus Diseases Work airway hyperresponsiveness airway inflammation airway remodeling base chemokine chemokine receptor crosslink curative treatments design human subject in vitro Assay in vitro activity in vivo inhibitor/antagonist innovation migration mouse model mutant novel peripheral blood prevent public health relevance receptor small molecule three dimensional structure tyrosine O-sulfate

项目摘要

DESCRIPTION (provided by applicant): Chronic obstructive lung diseases (COLD), such as asthma and COPD are major health issues, especially in modernized countries, and for which there are currently no curative therapies. Respiratory viral infections have been implicated in both development and exacerbation of COLD. Utilizing a mouse model of paramyxoviral infection, we have shown that infection with Sendai virus (SeV) leads to a long-lasting post-viral COLD with airway hyperreactivity and mucous cell metaplasia. This post-viral disease is dependent upon production of the chemokine CCL28 from lung dendritic cells. CCL28 has two receptors, CCR3 and CCR10, although it is not known through which of these receptors it exerts its effects in the SeV model. Blocking the effect of CCL28 in this model would be expected to prevent the development of the post-viral disease. We have recently developed a structure-based strategy to identify specific small molecule chemokine inhibitors, based on sulfotyrosine recognition pocket binding, that work by preventing receptor activation by the specific chemokine. We hypothesize that lung-specific CCL28 production is critical to the development of post-viral asthma, and that this process can be ablated by direct inhibition of CCL28's function. To test this hypothesis, we propose three specific aims: 1) Test the hypothesis that CCL28 activation of CCR10 leads to airway hyperresponsiveness and mucous cell metaplasia in a mouse model of obstructive lung disease. 2) Solve the 3D structure of CCL28 and identify important receptor recognition sites by NMR and mutagenesis. 3) Identify small molecule ligands that inhibit CCL28 activity in vitro and test their ability to prevent post-viral asthma in vivo. Upon completion of this project, we will have identified the chemokine receptor through which CCL28 mediates its action in the SeV model. Further, we will have developed at least one small molecule that inhibits CCL28 activity in both in vitro and in vivo assays. In the future, thee small molecule CCL28 antagonists could be further studied for potential use as a means to treat and/or prevent chronic obstructive lung disease in humans.

描述（由申请人提供）：慢性阻塞性肺病（COLD），例如哮喘和慢性阻塞性肺病（COPD）是主要的健康问题，尤其是在现代化国家，目前尚无治疗方法。呼吸道病毒感染与疾病的发展和发展有关。利用副粘病毒感染的小鼠模型，我们发现仙台病毒（SeV）感染会导致长期持续的病毒后感冒。这种病毒后疾病依赖于肺树突状细胞产生趋化因子 CCL28，CCL28 有两种受体：CCR3 和 CCR10，但尚不清楚它通过哪一种受体在肺中发挥作用。 SeV 模型。在该模型中阻断 CCL28 的作用有望预防病毒后疾病的发展。基于磺基酪氨酸识别口袋结合，识别特定的小分子趋化因子抑制剂，其通过阻止特定趋化因子激活受体来发挥作用。我们合作认为，肺部特异性 CCL28 的产生对于病毒后哮喘的发展至关重要，并且该过程可以为了检验这一假设，我们提出了三个具体目标：1) 检验 CCL28 激活 CCR10 导致气道的假设。阻塞性肺病小鼠模型中的高反应性和粘液细胞化生 2) 解析 CCL28 的 3D 结构并通过 NMR 和诱变鉴定重要的受体识别位点 3) 鉴定体外抑制 CCL28 活性的小分子配体并测试其能力。预防病毒后哮喘该项目完成后，我们将鉴定出 CCL28 在 SeV 模型中介导其作用的趋化因子受体，此外，我们将开发出至少一种在体外和体内测定中抑制 CCL28 活性的小分子。未来，可以进一步研究这些小分子 CCL28 拮抗剂，作为治疗和/或预防人类慢性阻塞性肺病的潜在用途。