Targeting CCL28 as therapy for obstructive lung disease

 描述（由申请人提供）：慢性阻塞性肺疾病（COLD），如哮喘和COPD是主要的健康问题，特别是在现代化国家，目前没有治愈性疗法。呼吸道病毒感染与感冒的发展和加重有关。利用副粘病毒感染的小鼠模型，我们已经表明，仙台病毒（SeV）的感染导致一个长期的病毒后感冒与气道高反应性和粘液细胞化生。这种病毒后疾病依赖于从肺树突状细胞产生趋化因子CCL 28。CCL 28有两种受体，CCR 3和CCR 10，尽管尚不清楚它在SeV模型中通过这些受体中的哪一种发挥作用。在该模型中阻断CCL 28的作用预期将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，基于磺基酪氨酸识别口袋结合，其通过阻止特定趋化因子的受体活化来起作用。我们假设肺特异性CCL 28的产生对病毒感染后哮喘的发展至关重要，并且这一过程可以通过直接抑制CCL 28的功能来消除。为了验证这一假设，我们提出了三个具体目标：1）在阻塞性肺病小鼠模型中验证CCL 28激活CCR 10导致气道高反应性和粘液细胞化生的假设。2)解析CCL 28的三维结构，并通过NMR和诱变鉴定重要的受体识别位点。3)在体外鉴定抑制CCL 28活性的小分子配体，并测试它们在体内预防病毒感染后哮喘的能力。 vivo.完成该项目后，我们将确定CCL 28在SeV模型中介导其作用的趋化因子受体。此外，我们将开发至少一种在体外和体内测定中抑制CCL 28活性的小分子。在未来，这些小分子CCL 28拮抗剂可以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的潜在用途。

 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.