Role of Thymic Stromal Lymphopoietin in Chronic Rhinosinusitis

胸腺基质淋巴细胞生成素在慢性鼻窦炎中的作用

• 批准号: 8994183
• 负责人: Atsushi Kato
• 金额: $ 38.63万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-15 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8994183
• 关键词: Adult; Affect; American; Animal Model; Antibiotic Therapy; Antibiotics; Asthma; Atopic Dermatitis; Biological; Biological Assay; Cells; Chronic Disease; Cleaved cell; Clinical; Complex; Dendritic Cells; Disease; Enzyme-Linked Immunosorbent Assay; Enzymes; Eosinophilia; Epithelial; Family; Genes; Genetic; Goals; Grant; Health; Health Care Costs; Human; Hypersensitivity; In Vitro; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Length; Living Costs; Lymphoid Cell; Mediating; Mediator of activation protein; Medical; Messenger RNA; Morbidity - disease rate; Nasal Polyps; Nasal obstruction present finding; Operative Surgical Procedures; Pathogenesis; Patients; Peptide Hydrolases; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Play; Post-Translational Protein Processing; Process; Production; Proprotein Convertases; Protein Precursors; Proteins; Quality of life; Regulation; Role; Serine Protease; Sinus; Steroids; Subtilisins; Symptoms; TSLP gene; Testing; Th2 Cells; Therapeutic Intervention; Tissues; United States; abstracting; base; chronic rhinosinusitis; cytokine; in vivo; novel; overexpression; research study; response; targeted treatment

DESCRIPTION (provided by applicant): Role of thymic stromal lymphopoietin in chronic rhinosinusitis Abstract: The overall goal of the studies in this project is to test the hypothesis hat Th2-related inflammatory responses in polypoid chronic rhinosinusitis are mediated, in part, by expression of the cytokine thymic stromal lymphopoietin (TSLP) 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 over 20 million Americans, and has a severe impact on patients' quality of life and healthcare costs. CRS is most commonly treated with antibiotics, steroids, and allergy medications. Due to poor responses to medical therapy, over 250,000 surgical procedures are performed 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 and is characterized by Th2-related inflammation including eosinophilia. However, the regulation of Th2 inflammation in CRSwNP is still largely unknown. In this proposal we will focus on TSLP, a cytokine that is recognized as a master regulator of Th2 inflammation. We have exciting evidence that TSLP is highly up-regulated in nasal polyps from patients with CRSwNP and high levels of TSLP are significantly correlated with eosinophilia and expression of Th2 cytokines in nasal polyps. In addition, we have found that nasal polyp extracts can truncate TSLP, and the truncated products may have more potent activity than the full-length form. We therefore hypothesize that TSLP 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 TSLP has species-specific activities and there is no animal model of CRS. Studies in Aim 1 will test the hypothesis that the family of serine proteases plays an important role in the posttranslational modification of TSLP in NPs. Studies in Aim 2 will test the hypothesis that posttranslational modification of TSLP by NP proteases results in higher TSLP activity than the full-length form. Studies in Aim 3 will test the hypothesi that TSLP and truncated TSLP play an important role in Th2-related inflammation in NPs. We believe that the proposed studies will reveal whether TSLP and truncated TSLP are potential targets for medical treatment of CRS.

描述（由申请人提供）：胸腺基质淋巴细胞素在慢性鼻辛愉悦性摘要中的作用：该项目研究的总体目的是测试息肉性鼻鼻炎中的假设hat Th2与细胞质胸腺质质乳胶质素（rympphopopopopopopoyietin ins rymphomphopoporietiys）的一部分介导的假设hat hat th2 hat th2相关的炎症反应。慢性鼻窦炎（CRS）是一种异质疾病，其特征是上呼吸道和鼻窦的局部炎症，对抗生素治疗无反应，并且至少持续了12周。它是美国成年人最常见的慢性疾病之一，影响了超过2000万美国人，并对患者的生活质量和医疗保健费用产生了严重影响。 CRS最常用抗生素，类固醇和过敏药物治疗。由于对医疗疗法的反应不佳，美国每年进行超过25万手术程序。因此，有必要更好地了解该疾病的致病机制，以产生新的医疗治疗。 CRS在临床上分类为具有鼻息肉（CRSWNP）和无鼻息肉（CRSSNP）的CRS。两种形式的特征都有强烈的炎症细胞浸润，它驱动了疾病的症状，但CRSWNP是两者中更严重的形式，其特征是Th2相关的炎症，包括嗜酸性粒细胞增多。但是，CRSWNP中Th2炎症的调节仍然很大程度上是未知的。在此提案中，我们将重点介绍TSLP，TSLP是一种被公认为是TH2炎症的主要调节剂的细胞因子。我们有令人兴奋的证据表明，TSLP在CRSWNP患者的鼻息中高度上调，而高水平的TSLP与嗜酸性粒细胞增多显着相关，并且在鼻息肉中Th2细胞因子的表达显着相关。此外，我们发现鼻息肉提取物可以截断TSLP，并且截短的产物可能比全长形式具有更多的有效活性。因此，我们假设TSLP及其截短产品在CRSWNP中起重要的致病作用。我们提出了使用体外和体内方法检验这一假设的实验。我们被迫在人类中检验这一假设，因为TSLP具有特异性活性，并且没有CR的动物模型。 AIM 1的研究将检验以下假设：丝氨酸蛋白酶家族在NPS中TSLP的翻译后修饰中起重要作用。 AIM 2中的研究将检验以下假设：NP蛋白酶对TSLP的翻译后修饰会导致TSLP活性高于全长形式。 AIM 3中的研究将测试TSLP和截断TSLP在NPS中与Th2相关的炎症中起重要作用的假设。我们认为，拟议的研究将揭示TSLP和TSLP是否是CRS医学治疗的潜在靶标。