Role of CC Chemokine Ligand 23 in Chronic Rhinosinusitis

描述(申请人提供)：本项目研究的总体目标是测试息肉状慢性鼻窦炎的炎症反应部分是由鼻窦组织中CCL23的表达所介导的假设。慢性鼻-鼻窦炎(CRS)是一种以上呼吸道和鼻窦局部炎症为特征的异质性疾病，对抗生素治疗无效，持续至少12周。它是美国成年人最常见的慢性病之一，影响着2,000-3,000万美国人，严重影响患者的生活质量和医疗费用。由于目前的药物-没有一种是FDA批准的专门用于治疗CRS的药物-疗效参差不齐，在美国每年需要进行超过25万次手术。因此，我们有必要更好地了解这种疾病的致病机制，以便产生新的药物治疗方法。CRS临床分为CRS伴鼻息肉(CRSwNP)和CRS不伴鼻息肉(CRSsNP)。这两种形式的特点都是强烈的炎症细胞渗透，这导致了疾病的症状，但CRSwNP是两种形式中更严重的一种。我们已经有了令人兴奋的发现，CC趋化因子配体23(CCL23)是CRSwNP患者鼻息肉中表达最高的基因之一。我们还发现，高水平的CCL23与鼻息肉中的嗜酸性粒细胞增多和巨噬细胞聚集显著相关。此外，我们还发现鼻息肉提取物可以截断CCL23。由于一个已知的截短形式的CCL23比其他已知的CCR1配体具有更高的CR1结合活性，我们推测CCL23及其截短产物在CRSwNP中起着重要的致病作用。我们建议使用体外和体内方法进行实验来验证这一假说。我们不得不在人类身上测试这一假说，因为在啮齿动物身上还没有发现CCL23基因。目标1中的研究将检验鼻息肉蛋白水解酶是否在CCL23截断中发挥重要作用。目标2的研究将检查CCL23的新截断产物是否具有比全长形式和已知截断形式更高的CCL23活性，并检查CCL23活性是否在鼻息肉中上调。目标3中的研究将检验截短的CCL23是否在鼻息肉的细胞募集中发挥重要作用。在这个项目中，我们将与ChemoCentryx的Juan Jaen博士合作，他是该领域的专家。我们相信，拟议的研究将回答CCL23、截短型CCL23和受体CCR1是否为CRS潜在的药物治疗靶点。

DESCRIPTION (provided by applicant): The overall goal of the studies in this project is to test the hypothesis that inflammatory responses in polypoid chronic rhinosinusitis are mediated, in part, by the expression of CCL23 in sinus tissue. Chronic rhinosinusitis (CRS) is a heterogeneous disease characterized by local inflammation of the upper airways and sinuses that is unresponsive to antibiotic therapy and which persists for at least 12 weeks. It is one of the most common chronic diseases in adults in the United States, affecting 20-30 million Americans, and has a severe impact on patients' quality of life and healthcare costs. Because current medications, none of which are FDA approved specifically for the treatment of CRS, have variable efficacy, over 250,000 surgical procedures are required annually in the United States. Therefore it is necessary that we better understand the pathogenic mechanisms of this disease in order to generate novel medical treatments. CRS is clinically classified into CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). Both forms are characterized by intense inflammatory cell infiltration which drives symptoms of the disease, but CRSwNP is the more severe form of the two. We have made exciting findings that CC chemokine ligand 23 (CCL23) is one of the most highly up-regulated genes in nasal polyps from patients with CRSwNP. We also have found that high levels of CCL23 are significantly correlated with eosinophilia and macrophage accumulation in nasal polyps. In addition, we have found that nasal polyp extracts can truncate CCL23. Since a known truncated form of CCL23 has higher CR1 binding activity than other known CCR1 ligands, we hypothesize that CCL23 and its truncated products play an important pathogenic role in CRSwNP. We propose experiments to test this hypothesis using in vitro and in vivo approaches. We are compelled to test this hypothesis in humans, because the CCL23 gene has not been found in rodents. Studies in Aim 1 will examine whether nasal polyp proteases play an important role in the truncation of CCL23. Studies in Aim 2 will examine whether novel truncated products of CCL23 have higher CCL23 activity than the full-length form and known truncated forms, and examine whether CCL23 activity is upregulated in nasal polyps. Studies in Aim 3 will examine whether truncated CCL23 plays an important role in cell recruitment in nasal polyps. In this project, we will collaborate with Dr. Juan Jaen of ChemoCentryx, who is an expert in the field. We believe that the proposed studies will answer whether CCL23, truncated CCL23 and the receptor CCR1 are potential targets for medical treatment of CRS.