Role of Thymic Stromal Lymphopoietin in Chronic Rhinosinusitis

描述(申请人提供)：胸腺间质淋巴生成素在慢性鼻-鼻窦炎中的作用摘要：本研究的总体目标是验证一种假说，即息肉样慢性鼻窦炎中Th2相关的炎症反应部分是通过细胞因子胸腺间质淋巴生成素(TSLP)在鼻窦组织中的表达来调节的。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2000多万美国人，并对患者的生活质量和医疗费用产生严重影响。CRS最常见的治疗方法是抗生素、类固醇和过敏药物。由于对药物治疗的不良反应，美国每年进行超过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，导致了疾病的症状，但CRSwNP是两种形式中更严重的一种，其特点是Th2相关的炎症，包括嗜酸性粒细胞增多症。然而，CRSwNP中Th2炎症的调节在很大程度上仍不清楚。在这项提案中，我们将重点关注TSLP，一种被公认为Th2炎症的主要调节因子。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，并且高水平的TSLP与鼻息肉中的嗜酸性粒细胞增多和Th2细胞因子的表达显著相关。此外，我们还发现，鼻息肉提取物可以截断TSLP，截断后的产物可能比全长产物具有更强的活性。因此，我们推测TSLP及其截短产物在CRSwNP中起重要的致病作用。我们建议使用体外和体内方法进行实验来验证这一假说。我们被迫在人类身上测试这一假说，因为TSLP具有物种特有的活动，而且没有CRS的动物模型。目标1中的研究将检验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。目标2中的研究将检验这一假设，即NP蛋白酶对TSLP的翻译后修饰会导致TSLP活性高于全长形式。目标3中的研究将检验TSLP和截短TSLP在NPs中Th2相关炎症中发挥重要作用的假设。我们相信，拟议的研究将揭示TSLP和截短TSLP是否为CRS的潜在药物治疗靶点。

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.