EPITHELIAL FUNCTION AND DYSFUNCTION IN CHRONIC SINUSITIS

据估计，慢性鼻窦炎影响着美国15%的人口，在过去十年中，这种疾病的患病率一直在上升。每年直接医疗费用保守估计为24亿美元；不包括每年近20万例鼻窦手术的相关费用。尽管慢性鼻窦炎发病率高，对卫生保健系统有重大影响，但对该病的病因和发病机制知之甚少。上皮增生和炎症是慢性鼻窦炎的一贯和显著特征。事实上，这些粘膜改变的CT或MRI成像可用于支持诊断。我们的中心假设是上皮细胞/粘膜功能障碍在慢性鼻窦炎的发病机制中起核心作用。这种功能障碍也可能是由于固有的遗传缺陷、环境影响，或者更有可能是两者的结合而引起的。该项目资助通过一系列项目来解决我们的中心假设的不同方面，提出了一个综合的、多学科的方法来检验这一中心假设。项目1评估一些受试者患慢性鼻窦炎的潜在遗传易感性。具体来说，将使用多种方法来进一步验证慢性鼻窦炎患者囊性纤维化跨膜调节因子的突变率高于健康人群的假设。项目2的重点是一个特定的环境因素，呼吸道病毒感染，作为一个触发因素，在改变上皮细胞功能的方式，在慢性鼻窦炎的发病机制中发挥作用。项目3表明，难治性慢性鼻窦炎患者表现出粘膜对组胺等刺激的低反应性，尽管存在严重的炎症。努力将集中于确定这种低反应性的机制，并评估是否存在黏膜低反应性的家族易感性。这三个项目将通过共享协议、专业知识和患者以及知识交流进行互动。所有三个项目都完全依赖核心中心来招募和确定患者和对照人群的特征，以及提供关键的支持服务。这些研究将确定对慢性鼻窦炎发病机制的重要见解，并可能导致治疗这一主要健康问题的新方法的发展。

Chronic rhinosinusitis effects an estimated 15% of the population of the United States, and the prevalence of this disease has been rising over the past decade. Annual direct medical costs are conservatively estimated at $2.4 billion; excluding the costs associated with the almost 200,000 sinus surgeries performed each year. Despite the high incidence of chronic rihnosinusitis and its major impact on the health care system, little is known regarding the etiology and pathogenesis of this disease. Epithelial hyperplasia and inflammation are consistent and striking features of chronic rhinosinusitis. Indeed, imaging of these mucosal changes by CT or MRI is used to support diagnosis. It is our central hypothesis that epithelial cell/mucosal dysfunction plays a central role in the pathogenesis of chronic rhinosinusitis. This dysfunction may also arise due to an inherent genetic defect(s), environmental influences, or, more likely, a combination of the two. This Program Grant presents an integrated, multidisciplinary approach to test this central hypothesis, through a series of projects which address differing aspects of our central hypothesis. Project 1 evaluates the potential genetic predisposition of some subjects to develop chronic rhinosinusitis. Specifically, a variey of approaches will be used to further test the hypothesis that patients with chronic rhinosinusitis have a higher rate of mutations in the cystic fibrosis transmembrane regulator than the healthy population. Project 2 focuses on the role of a specific environmental factor, respiratory viral infection, as a trigger factor in altering epithelial cell function in a manner that plays a role in the pathogenesis of chronic rhinosinusitis. Project 3 has demonstrated that patients with refractory chronic rhinosinusitis demonstrate mucosal hyporesponsiveness to stimuli such as histamine, despite the presence of profound inflammation. Efforts will focus on determining the mechanisms underlying this hyporesponsiveness and on evaluating if there is a familial predisposition for mucosal hyporesponsiveness. The three projects will interact by sharing protocols, expertise and patients, as well as through intellectual exchange. All three projects depend absolutely on the CORE for recruitment and characterization of patients and control populations, and for critical support services. These studies should determine important insights into the pathogenesis of chronic rhinosinusitis and may lead to the development of new approaches for the treatment of this major health problem.