Role of CC Chemokine Ligand 23 in Chronic Rhinosinusitis

描述（由申请人提供）：本项目研究的总体目标是验证息肉样慢性鼻窦炎的炎症反应部分由CCL23在鼻窦组织中的表达介导的假设。慢性鼻窦炎（CRS）是一种异质性疾病，其特征是上呼吸道和鼻窦局部炎症，对抗生素治疗无反应，并持续至少12周。它是美国成年人中最常见的慢性疾病之一，影响着2000万至3000万美国人，对患者的生活质量和医疗费用造成严重影响。由于目前的药物（没有一种是FDA专门批准用于治疗CRS的药物）疗效不一，美国每年需要进行超过25万例外科手术。因此，我们有必要更好地了解这种疾病的致病机制，以便产生新的医学治疗方法。CRS在临床上分为伴有鼻息肉的CRS （CRSwNP）和无鼻息肉的CRS （CRSsNP）。这两种形式的特征都是强烈的炎症细胞浸润，从而驱动疾病的症状，但CRSwNP是这两种形式中更严重的一种。我们已经取得了令人兴奋的发现，CC趋化因子配体23 （CCL23）是CRSwNP患者鼻息肉中最高度上调的基因之一。我们还发现，高水平的CCL23与鼻息肉嗜酸性粒细胞增多和巨噬细胞积聚显著相关。此外，我们发现鼻息肉提取物可以截断CCL23。由于已知的CCL23截断形式比其他已知的CCR1配体具有更高的CR1结合活性，我们假设CCL23及其截断产物在CRSwNP中起重要的致病作用。我们建议用体外和体内方法来验证这一假设。我们不得不在人类身上验证这个假设，因为在啮齿类动物身上还没有发现CCL23基因。Aim 1的研究将检验鼻息肉蛋白酶是否在CCL23截断中发挥重要作用。Aim 2的研究将检验CCL23的新型截断产物是否比全长形式和已知的截断形式具有更高的CCL23活性，并检验CCL23活性是否在鼻息肉中上调。Aim 3的研究将检验截断的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。我们相信所提出的研究将回答CCL23、截断的CCL23和受体CCR1是否是CRS医学治疗的潜在靶点。

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.