Targeting CCL28 as therapy for obstructive lung disease

 描述(申请人提供)：哮喘和慢性阻塞性肺病(COPD)等慢性阻塞性肺疾病(COLD)是主要的健康问题，特别是在现代化国家，目前还没有治愈的方法。呼吸道病毒感染与感冒的发展和恶化有关。利用副粘病毒感染的小鼠模型，我们已经证明，感染仙台病毒(SeV)会导致长期的病毒后感冒，并伴有呼吸道高反应性和粘液细胞化生。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，但尚不清楚它在SeV模型中是通过哪一种受体发挥作用的。在这个模型中，阻断CCL28的作用有望防止病毒后疾病的发展。我们最近开发了一种基于结构的策略来识别特定的小分子趋化因子抑制剂，该策略基于硫酪氨酸识别口袋结合，通过防止特定趋化因子激活受体来发挥作用。我们假设，肺特异性CCL28的产生在病毒后哮喘的发生发展中起关键作用，这一过程可以通过直接抑制CCL28的S功能而被阻断。为了验证这一假设，我们提出了三个具体目标：1)在阻塞性肺疾病小鼠模型中测试CCL28激活CCR10导致气道高反应和粘液细胞化生的假设。2)解析CCL28的三维结构，并通过核磁共振和诱变识别重要的受体识别位点。3)体外鉴定抑制CCL28活性的小分子配体，并检测其预防病毒后哮喘的能力 活着。在这个项目完成后，我们将确定趋化因子受体，CCL28通过该受体在SEV模型中介导其作用。此外，我们将在体外和体内试验中至少开发出一种抑制CCL28活性的小分子。在未来，这些小分子CCL28拮抗剂可能会被进一步研究，作为治疗和/或预防人类慢性阻塞性肺疾病的手段。

 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.