Role of CC Chemokine Ligand 23 in Chronic Rhinosinusitis

CC 趋化因子配体 23 在慢性鼻窦炎中的作用

• 批准号: 8444182
• 负责人: Atsushi Kato
• 金额: $ 22.06万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-23 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444182
• 关键词: Adult; Affect; American; Amino Acid Sequence; Amino Acids; Antibiotic Therapy; Antibodies; Base Sequence; Binding; Biological Assay; CC chemokine receptor 1; CCR1 gene; Cell Line; Cells; Chemotaxis; Chronic Disease; Cleaved cell; Conditioned Culture Media; Data; Dendritic Cells; Disease; Eosinophilia; FDA approved; Flow Cytometry; Genes; Goals; Grant; Health Care Costs; Human; In Vitro; Incubated; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Length; Ligands; Living Costs; Lymphocyte; Mediating; Medical; Messenger RNA; Morbidity - disease rate; Nasal Polyps; Nose; Operative Surgical Procedures; Pathogenesis; Patients; Peptide Hydrolases; Peptide Sequence Determination; Pharmaceutical Preparations; Play; Polyps; Post-Translational Protein Processing; Production; Protease Inhibitor; Proteins; Quality of life; Recombinants; Recruitment Activity; Reporting; Rodent; Role; Sinus; Symptoms; System; Testing; Therapeutic Intervention; Tissue Extracts; Tissues; United States; Western Blotting; base; beta-Chemokines; cell motility; cell type; chemokine; chemokine receptor; chronic rhinosinusitis; eosinophil; in vivo; macrophage; mast cell; migration; monocyte; neutralizing antibody; neutrophil; novel; overexpression; public health relevance; research study; response

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.

描述（由申请人提供）：该项目研究的总体目标是检验息肉样慢性鼻窦炎的炎症反应部分是由鼻窦组织中 CCL23 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，并且持续至少 12 周。它是美国成年人最常见的慢性疾病之一，影响着20-3000万美国人，对患者的生活质量和医疗费用产生严重影响。由于目前的药物（均未获得 FDA 批准专门用于治疗 CRS）疗效参差不齐，因此美国每年需要进行超过 250,000 例外科手术。因此，我们有必要更好地了解这种疾病的发病机制，以便产生新的医学治疗方法。 CRS临床上分为伴鼻息肉的CRS（CRSwNP）和不伴鼻息肉的CRS（CRSsNP）。 这两种形式的特点都是强烈的炎症细胞浸润，从而导致疾病症状，但 CRSwNP 是两种形式中更严重的形式。我们取得了令人兴奋的发现，即 CC 趋化因子配体 23 (CCL23) 是 CRSwNP 患者鼻息肉中上调程度最高的基因之一。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积聚显着相关。此外，我们发现鼻息肉提取物可以截短CCL23。由于已知的 CCL23 截短形式比其他已知的 CCR1 配体具有更高的 CR1 结合活性，因此我们假设 CCL23 及其截短产物在 CRSwNP 中发挥重要的致病作用。我们提出使用体外和体内方法来检验这一假设的实验。我们不得不在人类身上检验这一假设，因为在啮齿类动物中尚未发现 CCL23 基因。 目标 1 的研究将检验鼻息肉蛋白酶是否在 CCL23 截短中发挥重要作用。 目标 2 的研究将检验 CCL23 的新型截短产物是否比全长形式和已知的截短形式具有更高的 CCL23 活性，并检验 CCL23 活性在鼻息肉中是否上调。 目标 3 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、截短的CCL23和受体CCR1是否是CRS医学治疗的潜在靶点。