Role of Thymic Stromal Lymphopoietin in Chronic Rhinosinusitis

摘要：本项目研究的总体目标是验证息肉样慢性鼻窦炎中th2相关炎症反应部分是由细胞因子胸腺基质淋巴生成素（thymic stromal lymphoopoietin， TSLP）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多万美国人，对患者的生活质量和医疗费用产生严重影响。CRS最常用抗生素、类固醇和过敏药物治疗。由于药物治疗效果不佳，美国每年进行的外科手术超过25万例。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，其特征是th2相关炎症，包括嗜酸性粒细胞增多。然而，在CRSwNP中Th2炎症的调控在很大程度上仍然未知。在本提案中，我们将重点关注TSLP，一种被认为是Th2炎症的主要调节因子的细胞因子。我们有令人兴奋的证据表明，TSLP在CRSwNP患者的鼻息肉中高度上调，高水平的TSLP与鼻息肉中嗜酸性粒细胞增多和Th2细胞因子的表达显著相关。此外，我们发现鼻息肉提取物可以截断TSLP，截断后的产物可能比全长形式具有更强的活性。因此，我们假设TSLP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一假设，因为TSLP具有物种特异性活性，而CRS没有动物模型。Aim 1的研究将验证丝氨酸蛋白酶家族在NPs中TSLP的翻译后修饰中发挥重要作用的假设。Aim 2的研究将验证NP蛋白酶对TSLP的翻译后修饰导致TSLP活性高于全长形式的假设。Aim 3的研究将验证TSLP和截断TSLP在NPs中th2相关炎症中发挥重要作用的假设。我们相信这些研究将揭示TSLP和截断TSLP是否是CRS医学治疗的潜在靶点。

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.