Anti-inflammatory role of MUC1 mucin

铜绿假单胞菌(PA)是一种条件致病菌，可引起许多 重要的肺部疾病，包括肺炎和囊性纤维化(CF)。就中调而言，他的大调是j 患者发病和死亡的主要原因是浓缩性肺炎引起的呼吸道阻塞。 和顽固的粘液，会严重感染PA。因为PA暴露发生在呼吸系统 在正常人和慢性萎缩性胃炎患者中，这种病原体的“选择性”感染系统提示 存在一种致病机制，这种致病机制不存在于非慢性阻塞性肺疾病的呼吸道。一些不同之处 已经提出了一些理论来解释CF的病因。我们的实验室让这个有趣的 呼吸道上皮细胞表面MUC1粘蛋白是PA的特异性结合部位的观察 通过细菌鞭毛介导。MUC1糖蛋白的结构表明它作为一种 受体在与鞭毛蛋白相互作用后在细胞内传递信号。从基因上使用小鼠 我们的初步研究表明，经过修饰以阻断MUC1表达的小鼠(MUC1基因敲除小鼠) 对于野生型小鼠，Mud基因敲除动物表现出肺内PA清除增加和更多 支气管肺泡内白细胞募集和促炎细胞因子水平升高 PA鞭毛蛋白刺激后的大量液体。有趣的是，TLR5是另一种细胞表面受体THA 在与鞭毛蛋白结合后产生细胞内信号通路。基于这种相似性，我们 进行了额外的实验来研究‘ViUCL和TLR5之间的功能关系。我们 观察到MUC1在正常肺细胞中的表达抑制鞭毛蛋白-TLR5信号通路，但 不是CF型呼吸道上皮细胞。基于这些结果，我们形成了泰国MUC1是一种抗病毒的假设。 炎症细胞表面受体，至少部分通过拮抗鞭毛蛋白-1LR5信号起作用。 在这项提案中，我们将通过确定MUC1衰减T1..R5的机制来测试我们的理论 信号转导。该项目的成功完成将为以下方面提供重要的见解 MIJC1在炎症、先天免疫和PA感染早期在CF中的作用。

Pseiulomonus aeruginosa (PA) is an opportunistic bacterial pathogen responsible for a number of idinically important lung diseases including pneumonia and cystic fibrosis (CF). In the case of CF, .he major j jcause of morbidity and mortality among afflicted patients is airway obstruction due to the presence of thick and tenacious mucus that becomes heavily infected with PA. Because PA exposure occurs in therespiratory system of both normal and CF individuals, "selective"' infection by this pathogen among CF pi.tients suggests the presence of a disease-causing mechanism that is not present in non-CF airways. A number of di ffeivnt theories have been proposed to account for the etiology of CF. Our laboratory made theinteresting observation that MUC1 mucin on the surface of airway epithelial cells is a specific binding site for PA mediated through bacterial flagellin. The structureof the MUC1 glycoprotein suggests that it acts as a receptor to transmit signals intracellularly following interaction with flagellin. Using mice genetically modified to block MUC1 expression (MUC1 knockout mice), our preliminarystudies showed that, compared with wild type mice, Mud knockout animals exhibited increased PA clearance from the lungs and greater recruitment of airway leukocytes and higher levels of the proinflammatory cytokincs in bronchoalveolar lavuge fluid following PA flagellin stimulation. Interestingly,TLR5 is another cell surface receptor tha generates an intracellular signaling pathway following binding to flagellin. Based on this similarity, we conducted additional experiments to investigate the functional relationshipbetween 'ViUCl and TLR5. We observed that expression of MUC1 inhibited the flagellin-TLR5 signaling pathway in normal lung cells but not CF airway epithelial cells. Based on these results, we formed the hypothesis thai MUC1 is an anti- inflamrnatory cell surface receptor that acts, at least in part, through antagonism of flagellin-'1 LR5 signaling. In this proposal, we will test our theory by determining the mechanisms by which MUC1 attenuatesT1..R5 signal transduction. Successful completion of this project will provide important insights for the role of MIJC1 in inflammation, innate immunity, and the early stages of PA infection in CF.